Abstract
Pancreatic cancer, notorious for its late diagnosis and aggressive progression, poses a substantial challenge owing to scarce treatment alternatives. This review endeavors to furnish a holistic insight into pancreatic cancer, encompassing its epidemiology, genomic characterization, risk factors, diagnosis, therapeutic strategies, and treatment resistance mechanisms. We delve into identifying risk factors, including genetic predisposition and environmental exposures, and explore recent research advancements in precursor lesions and molecular subtypes of pancreatic cancer. Additionally, we highlight the development and application of multi-omics approaches in pancreatic cancer research and discuss the latest combinations of pancreatic cancer biomarkers and their efficacy. We also dissect the primary mechanisms underlying treatment resistance in this malignancy, illustrating the latest therapeutic options and advancements in the field. Conclusively, we accentuate the urgent demand for more extensive research to enhance the prognosis for pancreatic cancer patients.
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Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open 2021; 4(4): e214708
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021; 71(1): 7–33
Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet 2020; 395(10242): 2008–2020
Park W, Chawla A, O’Reilly EM. Pancreatic cancer: a review. JAMA 2021; 326(9): 851–862
Huang J, Lok V, Ngai CH, Zhang L, Yuan J, Lao XQ, Ng K, Chong C, Zheng ZJ, Wong MCS. Worldwide burden of, risk factors for, and trends in pancreatic cancer. Gastroenterology 2021; 160(3): 744–754
Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol 2015; 44(1): 186–198
Lynch SM, Vrieling A, Lubin JH, Kraft P, Mendelsohn JB, Hartge P, Canzian F, Steplowski E, Arslan AA, Gross M, Helzlsouer K, Jacobs EJ, LaCroix A, Petersen G, Zheng W, Albanes D, Amundadottir L, Bingham SA, Boffetta P, Boutron-Ruault MC, Chanock SJ, Clipp S, Hoover RN, Jacobs K, Johnson KC, Kooperberg C, Luo J, Messina C, Palli D, Patel AV, Riboli E, Shu XO, Rodriguez Suarez L, Thomas G, Tjønneland A, Tobias GS, Tong E, Trichopoulos D, Virtamo J, Ye W, Yu K, Zeleniuch-Jacquette A, Bueno-de-Mesquita HB, Stolzenberg-Solomon RZ. Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Am J Epidemiol 2009; 170(4): 403–413
Pang Y, Kartsonaki C, Guo Y, Bragg F, Yang L, Bian Z, Chen Y, Iona A, Millwood IY, Lv J, Yu C, Chen J, Li L, Holmes MV, Chen Z. Diabetes, plasma glucose and incidence of pancreatic cancer: a prospective study of 0.5 million Chinese adults and a meta-analysis of 22 cohort studies. Int J Cancer 2017; 140(8): 1781–1788
Canto MI, Almario JA, Schulick RD, Yeo CJ, Klein A, Blackford A, Shin EJ, Sanyal A, Yenokyan G, Lennon AM, Kamel IR, Fishman EK, Wolfgang C, Weiss M, Hruban RH, Goggins M. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 2018; 155(3): 740–751.e2
Corral JE, Mareth KF, Riegert-Johnson DL, Das A, Wallace MB. Diagnostic yield from screening asymptomatic individuals at high risk for pancreatic cancer: a meta-analysis of cohort studies. Clin Gastroenterol Hepatol 2019; 17(1): 41–53
Yuan C, Babic A, Khalaf N, Nowak JA, Brais LK, Rubinson DA, Ng K, Aguirre AJ, Pandharipande PV, Fuchs CS, Giovannucci EL, Stampfer MJ, Rosenthal MH, Sander C, Kraft P, Wolpin BM. Diabetes, weight change, and pancreatic cancer risk. JAMA Oncol 2020; 6(10): e202948
Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005; 129(2): 504–511
Gupta S, Vittinghoff E, Bertenthal D, Corley D, Shen H, Walter LC, McQuaid K. New-onset diabetes and pancreatic cancer. Clin Gastroenterol Hepatol 2006; 4(11): 1366–1372
Munigala S, Singh A, Gelrud A, Agarwal B. Predictors for pancreatic cancer diagnosis following new-onset diabetes mellitus. Clin Transl Gastroenterol 2015; 6(10): e118
Duell EJ, Lucenteforte E, Olson SH, Bracci PM, Li D, Risch HA, Silverman DT, Ji BT, Gallinger S, Holly EA, Fontham EH, Maisonneuve P, Bueno-de-Mesquita HB, Ghadirian P, Kurtz RC, Ludwig E, Yu H, Lowenfels AB, Seminara D, Petersen GM, La Vecchia C, Boffetta P. Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2012; 23(11): 2964–2970
Cai J, Chen H, Lu M, Zhang Y, Lu B, You L, Zhang T, Dai M, Zhao Y. Advances in the epidemiology of pancreatic cancer: trends, risk factors, screening, and prognosis. Cancer Lett 2021; 520: 1–11
Bosetti C, Lucenteforte E, Silverman DT, Petersen G, Bracci PM, Ji BT, Negri E, Li D, Risch HA, Olson SH, Gallinger S, Miller AB, Bueno-de-Mesquita HB, Talamini R, Polesel J, Ghadirian P, Baghurst PA, Zatonski W, Fontham E, Bamlet WR, Holly EA, Bertuccio P, Gao YT, Hassan M, Yu H, Kurtz RC, Cotterchio M, Su J, Maisonneuve P, Duell EJ, Boffetta P, La Vecchia C. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol 2012; 23(7): 1880–1888
Iodice S, Gandini S, Maisonneuve P, Lowenfels AB. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg 2008; 393(4): 535–545
Sung H, Siegel RL, Rosenberg PS, Jemal A. Emerging cancer trends among young adults in the USA: analysis of a population-based cancer registry. Lancet Public Health 2019; 4(3): e137–e147
Elena JW, Steplowski E, Yu K, Hartge P, Tobias GS, Brotzman MJ, Chanock SJ, Stolzenberg-Solomon RZ, Arslan AA, Bueno-de-Mesquita HB, Helzlsouer K, Jacobs EJ, LaCroix A, Petersen G, Zheng W, Albanes D, Allen NE, Amundadottir L, Bao Y, Boeing H, Boutron-Ruault MC, Buring JE, Gaziano JM, Giovannucci EL, Duell EJ, Hallmans G, Howard BV, Hunter DJ, Hutchinson A, Jacobs KB, Kooperberg C, Kraft P, Mendelsohn JB, Michaud DS, Palli D, Phillips LS, Overvad K, Patel AV, Sansbury L, Shu XO, Simon MS, Slimani N, Trichopoulos D, Visvanathan K, Virtamo J, Wolpin BM, Zeleniuch-Jacquotte A, Fuchs CS, Hoover RN, Gross M. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control 2013; 24(1): 13–25
Bosetti C, Rosato V, Li D, Silverman D, Petersen GM, Bracci PM, Neale RE, Muscat J, Anderson K, Gallinger S, Olson SH, Miller AB, Bas Bueno-de-Mesquita H, Scelo G, Janout V, Holcatova I, Lagiou P, Serraino D, Lucenteforte E, Fabianova E, Baghurst PA, Zatonski W, Foretova L, Fontham E, Bamlet WR, Holly EA, Negri E, Hassan M, Prizment A, Cotterchio M, Cleary S, Kurtz RC, Maisonneuve P, Trichopoulos D, Polesel J, Duell EJ, Boffetta P, La Vecchia C, Ghadirian P. Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium. Ann Oncol 2014; 25(10): 2065–2072
Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, English DR, Freudenheim JL, Fuchs CS, Giles GG, Giovannucci E, Hankinson SE, Horn-Ross PL, Leitzmann M, Männistö S, Marshall JR, McCullough ML, Miller AB, Reding DJ, Robien K, Rohan TE, Schatzkin A, Stevens VL, Stolzenberg-Solomon RZ, Verhage BA, Wolk A, Ziegler RG, Smith-Warner SA. Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomarkers Prev 2009; 18(3): 765–776
Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 2013; 144(6): 1252–1261
Xu JH, Fu JJ, Wang XL, Zhu JY, Ye XH, Chen SD. Hepatitis B or C viral infection and risk of pancreatic cancer: a meta-analysis of observational studies. World J Gastroenterol 2013; 19(26): 4234–4241
Kamiza AB, Su FH, Wang WC, Sung FC, Chang SN, Yeh CC. Chronic hepatitis infection is associated with extrahepatic cancer development: a nationwide population-based study in Taiwan. BMC Cancer 2016; 16(1): 861
Allison RD, Tong X, Moorman AC, Ly KN, Rupp L, Xu F, Gordon SC, Holmberg SD; Chronic Hepatitis Cohort Study (CHeCS) Investigators. Increased incidence of cancer and cancer-related mortality among persons with chronic hepatitis C infection, 2006–2010. J Hepatol 2015; 63(4): 822–828
Krull Abe S, Inoue M, Sawada N, Iwasaki M, Shimazu T, Yamaji T, Sasazuki S, Saito E, Tanaka Y, Mizokami M, Tsugane S; JPHC Study Group. Hepatitis B and C virus infection and risk of pancreatic cancer: a population-based cohort study (JPHC Study Cohort II). Cancer Epidemiol Biomarkers Prev 2016; 25(3): 555–557
Huang J, Zagai U, Hallmans G, Nyrén O, Engstrand L, Stolzenberg-Solomon R, Duell EJ, Overvad K, Katzke VA, Kaaks R, Jenab M, Park JY, Murillo R, Trichopoulou A, Lagiou P, Bamia C, Bradbury KE, Riboli E, Aune D, Tsilidis KK, Capellá G, Agudo A, Krogh V, Palli D, Panico S, Weiderpass E, Tjønneland A, Olsen A, Martínez B, Redondo-Sanchez D, Chirlaque MD, Hm Peeters P, Regnér S, Lindkvist B, Naccarati A, Ardanaz E, Larrañaga N, Boutron-Ruault MC, Rebours V, Barré A, Bueno-de-Mesquita HB, Ye W. Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: a nested case-control study. Int J Cancer 2017; 140(8): 1727–1735
GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2019; 4(12): 934–947
Zaitsu M, Kim Y, Lee HE, Takeuchi T, Kobayashi Y, Kawachi I. Occupational class differences in pancreatic cancer survival: a population-based cancer registry-based study in Japan. Cancer Med 2019; 8(6): 3261–3268
Fan X, Alekseyenko AV, Wu J, Peters BA, Jacobs EJ, Gapstur SM, Purdue MP, Abnet CC, Stolzenberg-Solomon R, Miller G, Ravel J, Hayes RB, Ahn J. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut 2018; 67(1): 120–127
Cotterchio M, Lowcock E, Hudson TJ, Greenwood C, Gallinger S. Association between allergies and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2014; 23(3): 469–480
Singhi AD, Ishida H, Ali SZ, Goggins M, Canto M, Wolfgang C, Meriden Z, Roberts N, Klein AP, Hruban RH. A histomorphologic comparison of familial and sporadic pancreatic cancers. Pancreatology 2015; 15(4): 387–391
Overbeek KA, Levink IJM, Koopmann BDM, Harinck F, Konings ICAW, Ausems MGEM, Wagner A, Fockens P, van Eijck CH, Groot Koerkamp B, Busch ORC, Besselink MG, Bastiaansen BAJ, van Driel LMJW, Erler NS, Vleggaar FP, Poley JW, Cahen DL, van Hooft JE, Bruno MJ; Dutch Familial Pancreatic Cancer Surveillance Study Group. Long-term yield of pancreatic cancer surveillance in high-risk individuals. Gut 2022; 71(6): 1152–1160
Wu C, Miao X, Huang L, Che X, Jiang G, Yu D, Yang X, Cao G, Hu Z, Zhou Y, Zuo C, Wang C, Zhang X, Zhou Y, Yu X, Dai W, Li Z, Shen H, Liu L, Chen Y, Zhang S, Wang X, Zhai K, Chang J, Liu Y, Sun M, Cao W, Gao J, Ma Y, Zheng X, Cheung ST, Jia Y, Xu J, Tan W, Zhao P, Wu T, Wang C, Lin D. Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet 2012; 44: 62–66
Holter S, Borgida A, Dodd A, Grant R, Semotiuk K, Hedley D, Dhani N, Narod S, Akbari M, Moore M, Gallinger S. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol 2015; 33(28): 3124–3129
Grant RC, Denroche RE, Borgida A, Virtanen C, Cook N, Smith AL, Connor AA, Wilson JM, Peterson G, Roberts NJ, Klein AP, Grimmond SM, Biankin A, Cleary S, Moore M, Lemire M, Zogopoulos G, Stein L, Gallinger S. Exome-wide association study of pancreatic cancer risk. Gastroenterology 2018; 154(3): 719–722.e3
Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, Lilyquist J, Na J, Moore R, Antwi SO, Bamlet WR, Chaffee KG, DiCarlo J, Wu Z, Samara R, Kasi PM, McWilliams RR, Petersen GM, Couch FJ. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 2018; 319(23): 2401–2409
Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021; 18(7): 493–502
Rainone M, Singh I, Salo-Mullen EE, Stadler ZK, O’Reilly EM. An emerging paradigm for germline testing in pancreatic ductal adenocarcinoma and immediate implications for clinical practice: a review. JAMA Oncol 2020; 6(5): 764–771
Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2020; 17(3): 153–168
Singh K, Pruski M, Bland R, Younes M, Guha S, Thosani N, Maitra A, Cash BD, McAllister F, Logsdon CD, Chang JT, Bailey-Lundberg JM. Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer. Lab Invest 2021; 101(2): 177–192
Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 2017; 32(2): 185–203.e13
Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, Mollaee M, Wagner KU, Koduru P, Yopp A, Choti MA, Yeo CJ, McCue P, White MA, Knudsen ES. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun 2015; 6(1): 6744
O’Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol 2019; 30(Suppl_8): viii36–viii40
Heining C, Horak P, Uhrig S, Codo PL, Klink B, Hutter B, Fröhlich M, Bonekamp D, Richter D, Steiger K, Penzel R, Endris V, Ehrenberg KR, Frank S, Kleinheinz K, Toprak UH, Schlesner M, Mandal R, Schulz L, Lambertz H, Fetscher S, Bitzer M, Malek NP, Horger M, Giese NA, Strobel O, Hackert T, Springfeld C, Feuerbach L, Bergmann F, Schröck E, von Kalle C, Weichert W, Scholl C, Ball CR, Stenzinger A, Brors B, Fröhling S, Glimm H. NRG1 fusions in KRAS wild-type pancreatic cancer. Cancer Discov 2018; 8(9): 1087–1095
Jones MR, Williamson LM, Topham JT, Lee MKC, Goytain A, Ho J, Denroche RE, Jang G, Pleasance E, Shen Y, Karasinska JM, McGhie JP, Gill S, Lim HJ, Moore MJ, Wong HL, Ng T, Yip S, Zhang W, Sadeghi S, Reisle C, Mungall AJ, Mungall KL, Moore RA, Ma Y, Knox JJ, Gallinger S, Laskin J, Marra MA, Schaeffer DF, Jones SJM, Renouf DJ. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma. Clin Cancer Res 2019; 25(15): 4674–4681
Hayashi A, Hong J, Iacobuzio-Donahue CA. The pancreatic cancer genome revisited. Nat Rev Gastroenterol Hepatol 2021; 18(7): 469–481
Connor AA, Denroche RE, Jang GH, Lemire M, Zhang A, Chan-Seng-Yue M, Wilson G, Grant RC, Merico D, Lungu I, Bartlett JMS, Chadwick D, Liang SB, Eagles J, Mbabaali F, Miller JK, Krzyzanowski P, Armstrong H, Luo X, Jorgensen LGT, Romero JM, Bavi P, Fischer SE, Serra S, Hafezi-Bakhtiari S, Caglar D, Roehrl MHA, Cleary S, Hollingsworth MA, Petersen GM, Thayer S, Law CHL, Nanji S, Golan T, Smith AL, Borgida A, Dodd A, Hedley D, Wouters BG, O’Kane GM, Wilson JM, Zogopoulos G, Notta F, Knox JJ, Gallinger S. Integration of genomic and transcriptional features in pancreatic cancer reveals increased cell cycle progression in metastases. Cancer Cell 2019; 35(2): 267–282.e7
Cao L, Huang C, Cui Zhou D, Hu Y, Lih TM, Savage SR, Krug K, Clark DJ, Schnaubelt M, Chen L, da Veiga Leprevost F, Eguez RV, Yang W, Pan J, Wen B, Dou Y, Jiang W, Liao Y, Shi Z, Terekhanova NV, Cao S, Lu RJ, Li Y, Liu R, Zhu H, Ronning P, Wu Y, Wyczalkowski MA, Easwaran H, Danilova L, Mer AS, Yoo S, Wang JM, Liu W, Haibe-Kains B, Thiagarajan M, Jewell SD, Hostetter G, Newton CJ, Li QK, Roehrl MH, Fenyö D, Wang P, Nesvizhskii AI, Mani DR, Omenn GS, Boja ES, Mesri M, Robles AI, Rodriguez H, Bathe OF, Chan DW, Hruban RH, Ding L, Zhang B, Zhang H.; Clinical Proteomic Tumor Analysis Consortium. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 2021; 184(19): 5031–5052.e26
Xie D, Wang Z, Sun B, Qu L, Zeng M, Feng L, Guo M, Wang G, Hao J, Zhou G. High frequency of alternative splicing variants of the oncogene Focal Adhesion Kinase in neuroendocrine tumors of the pancreas and breast. Front Med 2023; 17(5): 907–923
Liu M. Arid1a: a gatekeeper in the development of pancreatic cancer from a rare precursor lesion. Gastroenterology 2022; 163(2): 371–373
Christenson ES, Jaffee E, Azad NS. Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future. Lancet Oncol 2020; 21(3): e135–e145
Ahmed S, Bradshaw AD, Gera S, Dewan MZ, Xu R. The TGF-β/Smad4 signaling pathway in pancreatic carcinogenesis and its clinical significance. J Clin Med 2017; 6(1): 5
Chan-Seng-Yue M, Kim JC, Wilson GW, Ng K, Figueroa EF, O’Kane GM, Connor AA, Denroche RE, Grant RC, McLeod J, Wilson JM, Jang GH, Zhang A, Dodd A, Liang SB, Borgida A, Chadwick D, Kalimuthu S, Lungu I, Bartlett JMS, Krzyzanowski PM, Sandhu V, Tiriac H, Froeling FEM, Karasinska JM, Topham JT, Renouf DJ, Schaeffer DF, Jones SJM, Marra MA, Laskin J, Chetty R, Stein LD, Zogopoulos G, Haibe-Kains B, Campbell PJ, Tuveson DA, Knox JJ, Fischer SE, Gallinger S, Notta F. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat Genet 2020; 52(2): 231–240
Brunner M, Wu Z, Krautz C, Pilarsky C, Grützmann R, Weber GF. Current clinical strategies of pancreatic cancer treatment and open molecular questions. Int J Mol Sci 2019; 20(18): 4543
Gao J, Wang L, Xu J, Zheng J, Man X, Wu H, Jin J, Wang K, Xiao H, Li S, Li Z. Aberrant DNA methyltransferase expression in pancreatic ductal adenocarcinoma development and progression. J Exp Clin Cancer Res 2013; 32(1): 86
Zhang JJ, Zhu Y, Zhu Y, Wu JL, Liang WB, Zhu R, Xu ZK, Du Q, Miao Y. Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma. Clin Transl Oncol 2012; 14(2): 116–124
Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA; WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020; 76(2): 182–188
Zhang L, Chen D, Song D, Liu X, Zhang Y, Xu X, Wang X. Clinical and translational values of spatial transcriptomics. Signal Transduct Target Ther 2022; 7(1): 111
Schäfer D, Tomiuk S, Küster LN, Rawashdeh WA, Henze J, Tischler-Höhle G, Agorku DJ, Brauner J, Linnartz C, Lock D, Kaiser A, Herbel C, Eckardt D, Lamorte M, Lenhard D, Schüler J, Ströbel P, Missbach-Guentner J, Pinkert-Leetsch D, Alves F, Bosio A, Hardt O. Identification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma. Nat Commun 2021; 12(1): 1453
Hsieh WC, Budiarto BR, Wang YF, Lin CY, Gwo MC, So DK, Tzeng YS, Chen SY. Spatial multi-omics analyses of the tumor immune microenvironment. J Biomed Sci 2022; 29(1): 96
Moncada R, Barkley D, Wagner F, Chiodin M, Devlin JC, Baron M, Hajdu CH, Simeone DM, Yanai I. Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas. Nat Biotechnol 2020; 38(3): 333–342
Hwang WL, Jagadeesh KA, Guo JA, Hoffman HI, Yadollahpour P, Reeves JW, Mohan R, Drokhlyansky E, Van Wittenberghe N, Ashenberg O, Farhi SL, Schapiro D, Divakar P, Miller E, Zollinger DR, Eng G, Schenkel JM, Su J, Shiau C, Yu P, Freed-Pastor WA, Abbondanza D, Mehta A, Gould J, Lambden C, Porter CBM, Tsankov A, Dionne D, Waldman J, Cuoco MS, Nguyen L, Delorey T, Phillips D, Barth JL, Kem M, Rodrigues C, Ciprani D, Roldan J, Zelga P, Jorgji V, Chen JH, Ely Z, Zhao D, Fuhrman K, Fropf R, Beechem JM, Loeffler JS, Ryan DP, Weekes CD, Ferrone CR, Qadan M, Aryee MJ, Jain RK, Neuberg DS, Wo JY, Hong TS, Xavier R, Aguirre AJ, Rozenblatt-Rosen O, Mino-Kenudson M, Castillo CF, Liss AS, Ting DT, Jacks T, Regev A. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nat Genet 2022; 54(8): 1178–1191
Cui Zhou D, Jayasinghe RG, Chen S, Herndon JM, Iglesia MD, Navale P, Wendl MC, Caravan W, Sato K, Storrs E, Mo CK, Liu J, Southard-Smith AN, Wu Y, Naser Al Deen N, Baer JM, Fulton RS, Wyczalkowski MA, Liu R, Fronick CC, Fulton LA, Shinkle A, Thammavong L, Zhu H, Sun H, Wang LB, Li Y, Zuo C, McMichael JF, Davies SR, Appelbaum EL, Robbins KJ, Chasnoff SE, Yang X, Reeb AN, Oh C, Serasanambati M, Lal P, Varghese R, Mashl JR, Ponce J, Terekhanova NV, Yao L, Wang F, Chen L, Schnaubelt M, Lu RJ, Schwarz JK, Puram SV, Kim AH, Song SK, Shoghi KI, Lau KS, Ju T, Chen K, Chatterjee D, Hawkins WG, Zhang H, Achilefu S, Chheda MG, Oh ST, Gillanders WE, Chen F, DeNardo DG, Fields RC, Ding L. Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer. Nat Genet 2022; 54(9): 1390–1405
Tosti L, Hang Y, Debnath O, Tiesmeyer S, Trefzer T, Steiger K, Ten FW, Lukassen S, Ballke S, Kühl AA, Spieckermann S, Bottino R, Ishaque N, Weichert W, Kim SK, Eils R, Conrad C. Single-nucleus and in situ RNA-sequencing reveal cell topographies in the human pancreas. Gastroenterology 2021; 160(4): 1330–1344.e11
Barkley D, Moncada R, Pour M, Liberman DA, Dryg I, Werba G, Wang W, Baron M, Rao A, Xia B, França GS, Weil A, Delair DF, Hajdu C, Lund AW, Osman I, Yanai I. Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nat Genet 2022; 54(8): 1192–1201
Hayashi A, Fan J, Chen R, Ho YJ, Makohon-Moore AP, Lecomte N, Zhong Y, Hong J, Huang J, Sakamoto H, Attiyeh MA, Kohutek ZA, Zhang L, Boumiza A, Kappagantula R, Baez P, Bai J, Lisi M, Chadalavada K, Melchor JP, Wong W, Nanjangud GJ, Basturk O, O’Reilly EM, Klimstra DS, Hruban RH, Wood LD, Overholtzer M, Iacobuzio-Donahue CA. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nat Cancer 2020; 1(1): 59–74
Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grützmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM; Australian Pancreatic Cancer Genome Initiative; Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016; 531(7592): 47–52
Sun H, Zhang D, Huang C, Guo Y, Yang Z, Yao N, Dong X, Cheng R, Zhao N, Meng J, Sun B, Hao J. Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer. Cancer Biol Med 2021; 18(2): 616–630
Bell ATF, et al. PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration. bioRxiv 2022; 2022.07.16.500312
Agostini A, et al. Transcriptomic dissection of intraepithelial papillary mucinous neoplasms progression by spatial technologies identified novel markers of pancreatic carcinogenesis. bioRxiv 2022; 2022.10.12.511894
Sans M, Makino Y, Min J, Rajapakshe KI, Yip-Schneider M, Schmidt CM, Hurd MW, Burks JK, Gomez JA, Thege FI, Fahrmann JF, Wolff RA, Kim MP, Guerrero PA, Maitra A. Spatial transcriptomics of intraductal papillary mucinous neoplasms of the pancreas identifies NKX6-2 as a driver of gastric differentiation and indolent biological potential. Cancer Discov 2023; 13(8): 1844–1861
Peng J, Sun BF, Chen CY, Zhou JY, Chen YS, Chen H, Liu L, Huang D, Jiang J, Cui GS, Yang Y, Wang W, Guo D, Dai M, Guo J, Zhang T, Liao Q, Liu Y, Zhao YL, Han DL, Zhao Y, Yang YG, Wu W. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res 2019; 29(9): 725–738
Ma Z, Lytle NK, Chen B, Jyotsana N, Novak SW, Cho CJ, Caplan L, Ben-Levy O, Neininger AC, Burnette DT, Trinh VQ, Tan MCB, Patterson EA, Arrojo E Drigo R, Giraddi RR, Ramos C, Means AL, Matsumoto I, Manor U, Mills JC, Goldenring JR, Lau KS, Wahl GM, DelGiorno KE. Single-cell transcriptomics reveals a conserved metaplasia program in pancreatic injury. Gastroenterology 2022; 162(2): 604–620.e20
Lee JJ, Bernard V, Semaan A, Monberg ME, Huang J, Stephens BM, Lin D, Rajapakshe KI, Weston BR, Bhutani MS, Haymaker CL, Bernatchez C, Taniguchi CM, Maitra A, Guerrero PA. Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single-cell transcriptomics in real-world pancreatic cancer biopsies. Clin Cancer Res 2021; 27(21): 5912–5921
Lin W, Noel P, Borazanci EH, Lee J, Amini A, Han IW, Heo JS, Jameson GS, Fraser C, Steinbach M, Woo Y, Fong Y, Cridebring D, Von Hoff DD, Park JO, Han H. Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions. Genome Med 2020; 12(1): 80
Ligorio M, Sil S, Malagon-Lopez J, Nieman LT, Misale S, Di Pilato M, Ebright RY, Karabacak MN, Kulkarni AS, Liu A, Vincent Jordan N, Franses JW, Philipp J, Kreuzer J, Desai N, Arora KS, Rajurkar M, Horwitz E, Neyaz A, Tai E, Magnus NKC, Vo KD, Yashaswini CN, Marangoni F, Boukhali M, Fatherree JP, Damon LJ, Xega K, Desai R, Choz M, Bersani F, Langenbucher A, Thapar V, Morris R, Wellner UF, Schilling O, Lawrence MS, Liss AS, Rivera MN, Deshpande V, Benes CH, Maheswaran S, Haber DA, Fernandez-Del-Castillo C, Ferrone CR, Haas W, Aryee MJ, Ting DT. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 2019; 178(1): 160–175.e27
Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, Teinor JA, Belleau P, Biffi G, Lucito MS, Sivajothi S, Armstrong TD, Engle DD, Yu KH, Hao Y, Wolfgang CL, Park Y, Preall J, Jaffee EM, Califano A, Robson P, Tuveson DA. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov 2019; 9(8): 1102–1123
Foster DS, Januszyk M, Delitto D, Yost KE, Griffin M, Guo J, Guardino N, Delitto AE, Chinta M, Burcham AR, Nguyen AT, Bauer-Rowe KE, Titan AL, Salhotra A, Jones RE, da Silva O, Lindsay HG, Berry CE, Chen K, Henn D, Mascharak S, Talbott HE, Kim A, Nosrati F, Sivaraj D, Ransom RC, Matthews M, Khan A, Wagh D, Coller J, Gurtner GC, Wan DC, Wapnir IL, Chang HY, Norton JA, Longaker MT. Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer Cell 2022; 40(11): 1392–1406.e7
Dominguez CX, Müller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, Breart B, Foreman O, Bainbridge TW, Castiglioni A, Senbabaoglu Y, Modrusan Z, Liang Y, Junttila MR, Klijn C, Bourgon R, Turley SJ. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov 2020; 10(2): 232–253
Hutton C, Heider F, Blanco-Gomez A, Banyard A, Kononov A, Zhang X, Karim S, Paulus-Hock V, Watt D, Steele N, Kemp S, Hogg EKJ, Kelly J, Jackstadt RF, Lopes F, Menotti M, Chisholm L, Lamarca A, Valle J, Sansom OJ, Springer C, Malliri A, Marais R, Pasca di Magliano M, Zelenay S, Morton JP, Jørgensen C. Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell 2021; 39(9): 1227–1244.e20
Hosein AN, Huang H, Wang Z, Parmar K, Du W, Huang J, Maitra A, Olson E, Verma U, Brekken RA. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 2019; 4(16): e129212
Sherman MH, Beatty GL. Tumor microenvironment in pancreatic cancer pathogenesis and therapeutic resistance. Annu Rev Pathol 2023; 18(1): 123–148
Steele NG, Carpenter ES, Kemp SB, Sirihorachai VR, The S, Delrosario L, Lazarus J, Amir ED, Gunchick V, Espinoza C, Bell S, Harris L, Lima F, Irizarry-Negron V, Paglia D, Macchia J, Chu AKY, Schofield H, Wamsteker EJ, Kwon R, Schulman A, Prabhu A, Law R, Sondhi A, Yu J, Patel A, Donahue K, Nathan H, Cho C, Anderson MA, Sahai V, Lyssiotis CA, Zou W, Allen BL, Rao A, Crawford HC, Bednar F, Frankel TL, Pasca di Magliano M. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat Cancer 2020; 1(11): 1097–1112
Ho WJ, Erbe R, Danilova L, Phyo Z, Bigelow E, Stein-O’Brien G, Thomas DL2nd, Charmsaz S, Gross N, Woolman S, Cruz K, Munday RM, Zaidi N, Armstrong TD, Sztein MB, Yarchoan M, Thompson ED, Jaffee EM, Fertig EJ. Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways. Genome Biol 2021; 22(1): 154
Du Y, Cai Y, Lv Y, Zhang L, Yang H, Liu Q, Hong M, Teng Y, Tang W, Ma R, Wu J, Wu J, Wang Q, Chen H, Li K, Feng J. Single-cell RNA sequencing unveils the communications between malignant T and myeloid cells contributing to tumor growth and immunosuppression in cutaneous T-cell lymphoma. Cancer Lett 2022; 551: 215972
Shiau C, Su J, Guo JA, Hong TS, Wo JY, Jagadeesh KA, Hwang WL. Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution. Front Oncol 2022; 12: 929950
Du Y, Gu Z, Li Z, Yuan Z, Zhao Y, Zheng X, Bo X, Chen H, Wang C. Dynamic interplay between structural variations and 3D genome organization in pancreatic cancer. Adv Sci (Weinh) 2022; 9(18): e2200818
Alonso-Curbelo D, Ho YJ, Burdziak C, Maag JLV, Morris JP4th, Chandwani R, Chen HA, Tsanov KM, Barriga FM, Luan W, Tasdemir N, Livshits G, Azizi E, Chun J, Wilkinson JE, Mazutis L, Leach SD, Koche R, Pe’er D, Lowe SW. A gene-environment-induced epigenetic program initiates tumorigenesis. Nature 2021; 590(7847): 642–648
Burdziak C, Alonso-Curbelo D, Walle T, Reyes J, Barriga FM, Haviv D, Xie Y, Zhao Z, Zhao CJ, Chen HA, Chaudhary O, Masilionis I, Choo ZN, Gao V, Luan W, Wuest A, Ho YJ, Wei Y, Quail DF, Koche R, Mazutis L, Chaligné R, Nawy T, Lowe SW, Pe’er D. Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis. Science 2023; 380(6645): eadd5327
Guo F, Li L, Li J, Wu X, Hu B, Zhu P, Wen L, Tang F. Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells. Cell Res 2017; 27(8): 967–988
Fan X, Lu P, Wang H, Bian S, Wu X, Zhang Y, Liu Y, Fu D, Wen L, Hao J, Tang F. Integrated single-cell multiomics analysis reveals novel candidate markers for prognosis in human pancreatic ductal adenocarcinoma. Cell Discov 2022; 8(1): 13
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K, Quinn MC, Robertson AJ, Fadlullah MZ, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, Manning S, Nourse C, Nourbakhsh E, Wani S, Wilson PJ, Markham E, Cloonan N, Anderson MJ, Fink JL, Holmes O, Kazakoff SH, Leonard C, Newell F, Poudel B, Song S, Taylor D, Waddell N, Wood S, Xu Q, Wu J, Pinese M, Cowley MJ, Lee HC, Jones MD, Nagrial AM, Humphris J, Chantrill LA, Chin V, Steinmann AM, Mawson A, Humphrey ES, Colvin EK, Chou A, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Pettitt JA, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Jamieson NB, Graham JS, Niclou SP, Bjerkvig R, Grützmann R, Aust D, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Falconi M, Zamboni G, Tortora G, Tempero MA; Australian Pancreatic Cancer Genome Initiative; Gill AJ, Eshleman JR, Pilarsky C, Scarpa A, Musgrove EA, Pearson JV, Biankin AV, Grimmond SM. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518(7540): 495–501
Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, Rashid NU, Williams LA, Eaton SC, Chung AH, Smyla JK, Anderson JM, Kim HJ, Bentrem DJ, Talamonti MS, Iacobuzio-Donahue CA, Hollingsworth MA, Yeh JJ. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 2015; 47(10): 1168–1178
Puleo F, Nicolle R, Blum Y, Cros J, Marisa L, Demetter P, Quertinmont E, Svrcek M, Elarouci N, Iovanna J, Franchimont D, Verset L, Galdon MG, Devière J, de Reyniès A, Laurent-Puig P, Van Laethem JL, Bachet JB, Maréchal R. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 2018; 155(6): 1999–2013.e3
Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, Cooc J, Weinkle J, Kim GE, Jakkula L, Feiler HS, Ko AH, Olshen AB, Danenberg KL, Tempero MA, Spellman PT, Hanahan D, Gray JW. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 2011; 17(4): 500–503
Maurer C, Holmstrom SR, He J, Laise P, Su T, Ahmed A, Hibshoosh H, Chabot JA, Oberstein PE, Sepulveda AR, Genkinger JM, Zhang J, Iuga AC, Bansal M, Califano A, Olive KP. Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes. Gut 2019; 68(6): 1034–1043
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O’Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C.; TRACERx Consortium. Tracking the evolution of non-small-cell lung cancer. N Engl J Med 2017; 376(22): 2109–2121
Rashid NU, Peng XL, Jin C, Moffitt RA, Volmar KE, Belt BA, Panni RZ, Nywening TM, Herrera SG, Moore KJ, Hennessey SG, Morrison AB, Kawalerski R, Nayyar A, Chang AE, Schmidt B, Kim HJ, Linehan DC, Yeh JJ. Purity independent subtyping of tumors (PurIST), a clinically robust, single-sample classifier for tumor subtyping in pancreatic cancer. Clin Cancer Res 2020; 26(1): 82–92
Ullman NA, Burchard PR, Dunne RF, Linehan DC. Immunologic strategies in pancreatic cancer: making cold tumors hot. J Clin Oncol 2022; 40(24): 2789–2805
Li X, Gulati M, Larson AC, Solheim JC, Jain M, Kumar S, Batra SK. Immune checkpoint blockade in pancreatic cancer: trudging through the immune desert. Semin Cancer Biol 2022; 86(Pt 2): 14–27
Nagaraju GP, Malla RR, Basha R, Motofei IG. Contemporary clinical trials in pancreatic cancer immunotherapy targeting PD-1 and PD-L1. Semin Cancer Biol 2022; 86(Pt 3): 616–621
Xue R, Zhang Q, Cao Q, Kong R, Xiang X, Liu H, Feng M, Wang F, Cheng J, Li Z, Zhan Q, Deng M, Zhu J, Zhang Z, Zhang N. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 2022; 612(7938): 141–147
Raghavan S, Winter PS, Navia AW, Williams HL, DenAdel A, Lowder KE, Galvez-Reyes J, Kalekar RL, Mulugeta N, Kapner KS, Raghavan MS, Borah AA, Liu N, Väyrynen SA, Costa AD, Ng RWS, Wang J, Hill EK, Ragon DY, Brais LK, Jaeger AM, Spurr LF, Li YY, Cherniack AD, Booker MA, Cohen EF, Tolstorukov MY, Wakiro I, Rotem A, Johnson BE, McFarland JM, Sicinska ET, Jacks TE, Sullivan RJ, Shapiro GI, Clancy TE, Perez K, Rubinson DA, Ng K, Cleary JM, Crawford L, Manalis SR, Nowak JA, Wolpin BM, Hahn WC, Aguirre AJ, Shalek AK. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell 2021; 184(25): 6119–6137.e26
Grimont A, Leach SD, Chandwani R. Uncertain beginnings: acinar and ductal cell plasticity in the development of pancreatic cancer. Cell Mol Gastroenterol Hepatol 2022; 13(2): 369–382
Messal HA, Alt S, Ferreira RMM, Gribben C, Wang VM, Cotoi CG, Salbreux G, Behrens A. Tissue curvature and apicobasal mechanical tension imbalance instruct cancer morphogenesis. Nature 2019; 566(7742): 126–130
Li S, Xie K. Ductal metaplasia in pancreas. Biochim Biophys Acta Rev Cancer 2022; 1877(2): 188698
Parte S, Nimmakayala RK, Batra SK, Ponnusamy MP. Acinar to ductal cell trans-differentiation: a prelude to dysplasia and pancreatic ductal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877(1): 188669
Del Poggetto E, Ho IL, Balestrieri C, Yen EY, Zhang S, Citron F, Shah R, Corti D, Diaferia GR, Li CY, Loponte S, Carbone F, Hayakawa Y, Valenti G, Jiang S, Sapio L, Jiang H, Dey P, Gao S, Deem AK, Rose-John S, Yao W, Ying H, Rhim AD, Genovese G, Heffernan TP, Maitra A, Wang TC, Wang L, Draetta GF, Carugo A, Natoli G, Viale A. Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. Science 2021; 373(6561): eabj0486
De La O JP, Emerson LL, Goodman JL, Froebe SC, Illium BE, Curtis AB, Murtaugh LC. Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA 2008; 105(48): 18907–18912
Huang H, He M, Zhang Y, Zhang B, Niu Z, Zheng Y, Li W, Cui P, Wang X, Sun Q. Identification and validation of heterotypic cell-in-cell structure as an adverse prognostic predictor for young patients of resectable pancreatic ductal adenocarcinoma. Signal Transduct Target Ther 2020; 5(1): 246
Song J, Ruze R, Chen Y, Xu R, Yin X, Wang C, Xu Q, Zhao Y. Construction of a novel model based on cell-in-cell-related genes and validation of KRT7 as a biomarker for predicting survival and immune microenvironment in pancreatic cancer. BMC Cancer 2022; 22(1): 894
Xi NM, Li JJ. Benchmarking computational doublet-detection methods for single-cell RNA sequencing data. Cell Syst 2021; 12(2): 176–194.e6
Bais AS, Kostka D. scds: computational annotation of doublets in single-cell RNA sequencing data. Bioinformatics 2020; 36(4): 1150–1158
Singh VK, Yadav D, Garg PK. Diagnosis and management of chronic pancreatitis: a review. JAMA 2019; 322(24): 2422–2434
Greenhalf W, Lévy P, Gress T, Rebours V, Brand RE, Pandol S, Chari S, Jørgensen MT, Mayerle J, Lerch MM, Hegyi P, Kleeff J, Castillo CF, Isaji S, Shimosegawa T, Sheel A, Halloran CM, Garg P, Takaori K, Besselink MG, Forsmark CE, Wilcox CM, Maisonneuve P, Yadav D, Whitcomb D, Neoptolemos J; Working group for the International (IAP–APA–JPS–EPC) Consensus Guidelines for Chronic Pancreatitis. International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club. Pancreatology 2020; 20(5): 910–918
Hegyi P, Párniczky A, Lerch MM, Sheel ARG, Rebours V, Forsmark CE, Del Chiaro M, Rosendahl J, de-Madaria E, Szücs Á, Takaori K, Yadav D, Gheorghe C, Rakonczay Z Jr, Molero X, Inui K, Masamune A, Fernandez-Del Castillo C, Shimosegawa T, Neoptolemos JP, Whitcomb DC, Sahin-Tóth M; Working Group for the International (IAP–APA–JPS–EPC) Consensus Guidelines for Chronic Pancreatitis. International consensus guidelines for risk factors in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club. Pancreatology 2020; 20(4): 579–585
Sun C, Liu M, An W, Mao X, Jiang H, Zou W, Wu H, Liao Z, Li Z. Heterozygous Spink1 c.194+2T>C mutant mice spontaneously develop chronic pancreatitis. Gut 2020; 69(5): 967–968
Geisz A, Sahin-Tóth M. A preclinical model of chronic pancreatitis driven by trypsinogen autoactivation. Nat Commun 2018; 9(1): 5033
Hegyi E, Sahin-Tóth M. Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice. Gut 2019; 68(2): 301–312
Kichler A, Jang S. Chronic pancreatitis: epidemiology, diagnosis, and management updates. Drugs 2020; 80(12): 1155–1168
Storz P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2017; 14(5): 296–304
Westphalen CB, Takemoto Y, Tanaka T, Macchini M, Jiang Z, Renz BW, Chen X, Ormanns S, Nagar K, Tailor Y, May R, Cho Y, Asfaha S, Worthley DL, Hayakawa Y, Urbanska AM, Quante M, Reichert M, Broyde J, Subramaniam PS, Remotti H, Su GH, Rustgi AK, Friedman RA, Honig B, Califano A, Houchen CW, Olive KP, Wang TC. Dclk1 defines quiescent pancreatic progenitors that promote injury-induced regeneration and tumorigenesis. Cell Stem Cell 2016; 18(4): 441–455
Bailey JM, Alsina J, Rasheed ZA, McAllister FM, Fu YY, Plentz R, Zhang H, Pasricha PJ, Bardeesy N, Matsui W, Maitra A, Leach SD. DCLK1 marks a morphologically distinct subpopulation of cells with stem cell properties in preinvasive pancreatic cancer. Gastroenterology 2014; 146(1): 245–256
Ferguson FM, Nabet B, Raghavan S, Liu Y, Leggett AL, Kuljanin M, Kalekar RL, Yang A, He S, Wang J, Ng RWS, Sulahian R, Li L, Poulin EJ, Huang L, Koren J, Dieguez-Martinez N, Espinosa S, Zeng Z, Corona CR, Vasta JD, Ohi R, Sim T, Kim ND, Harshbarger W, Lizcano JM, Robers MB, Muthaswamy S, Lin CY, Look AT, Haigis KM, Mancias JD, Wolpin BM, Aguirre AJ, Hahn WC, Westover KD, Gray NS. Discovery of a selective inhibitor of doublecortin like kinase 1. Nat Chem Biol 2020; 16(6): 635–643
Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra J, Biankin AV, Brosens LA, Fukushima N, Goggins M, Hruban RH, Kato Y, Klimstra DS, Klöppel G, Krasinskas A, Longnecker DS, Matthaei H, Offerhaus GJ, Shimizu M, Takaori K, Terris B, Yachida S, Esposito I, Furukawa T; Baltimore Consensus Meeting. A revised classification system and recommendations from the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas. Am J Surg Pathol 2015; 39(12): 1730–1741
Liffers ST, Godfrey L, Frohn L, Haeberle L, Yavas A, Vesce R, Goering W, Opitz FV, Stoecklein N, Knoefel WT, Schlitter AM, Klöppel G, Espinet E, Trumpp A, Siveke JT, Esposito I. Molecular heterogeneity and commonalities in pancreatic cancer precursors with gastric and intestinal phenotype. Gut 2023; 72(3): 522–534
Felsenstein M, Noë M, Masica DL, Hosoda W, Chianchiano P, Fischer CG, Lionheart G, Brosens LAA, Pea A, Yu J, Gemenetzis G, Groot VP, Makary MA, He J, Weiss MJ, Cameron JL, Wolfgang CL, Hruban RH, Roberts NJ, Karchin R, Goggins MG, Wood LD. IPMNs with co-occurring invasive cancers: neighbours but not always relatives. Gut 2018; 67(9): 1652–1662
Scarpa A, Real FX, Luchini C. Genetic unrelatedness of co-occurring pancreatic adenocarcinomas and IPMNs challenges current views of clinical management. Gut 2018; 67(9): 1561–1563
Mafficini A, Simbolo M, Shibata T, Hong SM, Pea A, Brosens LA, Cheng L, Antonello D, Sciammarella C, Cantù C, Mattiolo P, Taormina SV, Malleo G, Marchegiani G, Sereni E, Corbo V, Paolino G, Ciaparrone C, Hiraoka N, Pallaoro D, Jansen C, Milella M, Salvia R, Lawlor RT, Adsay V, Scarpa A, Luchini C. Integrative characterization of intraductal tubulopapillary neoplasm (ITPN) of the pancreas and associated invasive adenocarcinoma. Mod Pathol 2022; 35(12): 1929–1943
Yamaguchi H, Shimizu M, Ban S, Koyama I, Hatori T, Fujita I, Yamamoto M, Kawamura S, Kobayashi M, Ishida K, Morikawa T, Motoi F, Unno M, Kanno A, Satoh K, Shimosegawa T, Orikasa H, Watanabe T, Nishimura K, Ebihara Y, Koike N, Furukawa T. Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 2009; 33(8): 1164–1172
Paolino G, Esposito I, Hong SM, Basturk O, Mattiolo P, Kaneko T, Veronese N, Scarpa A, Adsay V, Luchini C. Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors. Histopathology 2022; 81(3): 297–309
Fukunaga Y, Fukuda A, Omatsu M, Namikawa M, Sono M, Masuda T, Araki O, Nagao M, Yoshikawa T, Ogawa S, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Ferrer J, Tsuruyama T, Masui T, Hatano E, Seno H. Loss of Arid1a and Pten in pancreatic ductal cells induces intraductal tubulopapillary neoplasm via the YAP/TAZ pathway. Gastroenterology 2022; 163(2): 466–480.e6
Basturk O, Berger MF, Yamaguchi H, Adsay V, Askan G, Bhanot UK, Zehir A, Carneiro F, Hong SM, Zamboni G, Dikoglu E, Jobanputra V, Wrzeszczynski KO, Balci S, Allen P, Ikari N, Takeuchi S, Akagawa H, Kanno A, Shimosegawa T, Morikawa T, Motoi F, Unno M, Higuchi R, Yamamoto M, Shimizu K, Furukawa T, Klimstra DS. Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma. Mod Pathol 2017; 30(12): 1760–1772
Sakihama K, Koga Y, Yamamoto T, Shimada Y, Yamada Y, Kawat J, Shindo K, Nakamura M, Oda Y. RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm. Virchows Arch 2022; 480(6): 1189–1199
Conner JR, Enríquez AM, Kenudso MM, Garcia E, Pitman MB, Sholl LM, Srivastava A, Doyle LA. Genomic characterization of low- and high-grade pancreatic mucinous cystic neoplasms reveals recurrent kras alterations in “high-risk” lesions. Pancreas 2017; 46(5): 665–671
Maimaitiaili Y, Fukumura Y, Hirabayashi K, Kinowaki Y, Naito Y, Saito A, Rong L, Nakahodo J, Yao T. Investigation of -PRKACA/-PRKACB fusion genes in oncocytic tumors of the pancreatobiliary and other systems. Virchows Arch 2022; 481(6): 865–876
Singhi AD, Wood LD, Parks E, Torbenson MS, Felsenstein M, Hruban RH, Nikiforova MN, Wald AI, Kaya C, Nikiforov YE, Favazza L, He J, McGrath K, Fasanella KE, Brand RE, Lennon AM, Furlan A, Dasyam AK, Zureikat AH, Zeh HJ, Lee K, Bartlett DL, Slivka A. Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct. Gastroenterology 2020; 158(3): 573–582.e2
Wang T, Askan G, Adsay V, Allen P, Jarnagin WR, Memis B, Sigel C, Seven IE, Klimstra DS, Basturk O. Intraductal oncocytic papillary neoplasms: clinical-pathologic characterization of 24 cases, with an emphasis on associated invasive carcinomas. Am J Surg Pathol 2019; 43(5): 656–661
Ferreira RMM, Sancho R, Messal HA, Nye E, Spencer-Dene B, Stone RK, Stamp G, Rosewell I, Quaglia A, Behrens A. Duct- and acinar-derived pancreatic ductal adenocarcinomas show distinct tumor progression and marker expression. Cell Rep 2017; 21(4): 966–978
Makohon-Moore AP, Matsukuma K, Zhang M, Reiter JG, Gerold JM, Jiao Y, Sikkema L, Attiyeh MA, Yachida S, Sandone C, Hruban RH, Klimstra DS, Papadopoulos N, Nowak MA, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA. Precancerous neoplastic cells can move through the pancreatic ductal system. Nature 2018; 561(7722): 201–205
Hutchings D, Waters KM, Weiss MJ, Wolfgang CL, Makary MA, He J, Cameron JL, Wood LD, Hruban RH. Cancerization of the pancreatic ducts: demonstration of a common and under-recognized process using immunolabeling of paired duct lesions and invasive pancreatic ductal adenocarcinoma for p53 and Smad4 expression. Am J Surg Pathol 2018; 42(11): 1556–1561
Matsuda Y, Furukawa T, Yachida S, Nishimura M, Seki A, Nonaka K, Aida J, Takubo K, Ishiwata T, Kimura W, Arai T, Mino-Kenudson M. The prevalence and clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia: autopsy study evaluating the entire pancreatic parenchyma. Pancreas 2017; 46(5): 658–664
Goggins M, Hruban RH, Kern SE. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications. Am J Pathol 2000; 156(5): 1767–1771
Sharma GG, Okada Y, Von Hoff D, Goel A. Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2021; 75: 153–168
Al-Shaheri FN, Alhamdani MSS, Bauer AS, Giese N, Büchler MW, Hackert T, Hoheisel JD. Blood biomarkers for differential diagnosis and early detection of pancreatic cancer. Cancer Treat Rev 2021; 96: 102193
Luo G, Jin K, Deng S, Cheng H, Fan Z, Gong Y, Qian Y, Huang Q, Ni Q, Liu C, Yu X. Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter. Biochim Biophys Acta Rev Cancer 2021; 1875(2): 188409
Deng Y, Sun Z, Wang L, Wang M, Yang J, Li G. Biosensor-based assay of exosome biomarker for early diagnosis of cancer. Front Med 2022; 16(2): 157–175
Berger AW, Schwerdel D, Reinacher-Schick A, Uhl W, Algül H, Friess H, Janssen KP, König A, Ghadimi M, Gallmeier E, Bartsch DK, Geissler M, Staib L, Tannapfel A, Kleger A, Beutel A, Schulte LA, Kornmann M, Ettrich TJ, Seufferlein T. A blood-based multi marker assay supports the differential diagnosis of early-stage pancreatic cancer. Theranostics 2019; 9(5): 1280–1287
Thibault B, Ramos-Delgado F, Pons-Tostivint E, Therville N, Cintas C, Arcucci S, Cassant-Sourdy S, Reyes-Castellanos G, Tosolini M, Villard AV, Cayron C, Baer R, Bertrand-Michel J, Pagan D, Ferreira Da Mota D, Yan H, Falcomatà C, Muscari F, Bournet B, Delord JP, Aksoy E, Carrier A, Cordelier P, Saur D, Basset C, Guillermet-Guibert J. Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component. EMBO Mol Med 2021; 13(7): e13502
Groot VP, Mosier S, Javed AA, Teinor JA, Gemenetzis G, Ding D, Haley LM, Yu J, Burkhart RA, Hasanain A, Debeljak M, Kamiyama H, Narang A, Laheru DA, Zheng L, Lin MT, Gocke CD, Fishman EK, Hruban RH, Goggins MG, Molenaar IQ, Cameron JL, Weiss MJ, Velculescu VE, He J, Wolfgang CL, Eshleman JR. Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clin Cancer Res 2019; 25(16): 4973–4984
Li H, Warden AR, Su W, He J, Zhi X, Wang K, Zhu L, Shen G, Ding X. Highly sensitive and portable mRNA detection platform for early cancer detection. J Nanobiotechnology 2021; 19(1): 287
Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523(7559): 177–182
Nagata N, Nishijima S, Kojima Y, Hisada Y, Imbe K, Miyoshi-Akiyama T, Suda W, Kimura M, Aoki R, Sekine K, Ohsugi M, Miki K, Osawa T, Ueki K, Oka S, Mizokami M, Kartal E, Schmidt TSB, Molina-Montes E, Estudillo L, Malats N, Trebicka J, Kersting S, Langheinrich M, Bork P, Uemura N, Itoi T, Kawai T. Metagenomic identification of microbial signatures predicting pancreatic cancer from a multinational study. Gastroenterology 2022; 163(1): 222–238
Pang Y, Wang C, Lu L, Wang C, Sun Z, Xiao R. Dual-SERS biosensor for one-step detection of microRNAs in exosome and residual plasma of blood samples for diagnosing pancreatic cancer. Biosens Bioelectron 2019; 130: 204–213
Sharma GG, Okada Y, Von Hoff D, Goel A. Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2021; 75: 153–168
Jin F, Yang L, Wang W, Yuan N, Zhan S, Yang P, Chen X, Ma T, Wang Y. A novel class of tsRNA signatures as biomarkers for diagnosis and prognosis of pancreatic cancer. Mol Cancer 2021; 20(1): 95
Zhan S, Yang P, Zhou S, Xu Y, Xu R, Liang G, Zhang C, Chen X, Yang L, Jin F, Wang Y. Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis. Front Med 2022; 16(2): 216–226
Majumder S, Taylor WR, Foote PH, Berger CK, Wu CW, Mahoney DW, Bamlet WR, Burger KN, Postier N, de la Fuente J, Doering KA, Lidgard GP, Allawi HT, Petersen GM, Chari ST, Ahlquist DA, Kisiel JB. High detection rates of pancreatic cancer across stages by plasma assay of novel methylated DNA markers and CA19-9. Clin Cancer Res 2021; 27(9): 2523–2532
Kim Y, Yeo I, Huh I, Kim J, Han D, Jang JY, Kim Y. Development and multiple validation of the protein multi-marker panel for diagnosis of pancreatic cancer. Clin Cancer Res 2021; 27(8): 2236–2245
Mahajan UM, Oehrle B, Sirtl S, Alnatsha A, Goni E, Regel I, Beyer G, Vornhülz M, Vielhauer J, Chromik A, Bahra M, Klein F, Uhl W, Fahlbusch T, Distler M, Weitz J, Grützmann R, Pilarsky C, Weiss FU, Adam MG, Neoptolemos JP, Kalthoff H, Rad R, Christiansen N, Bethan B, Kamlage B, Lerch MM, Mayerle J. Independent validation and assay standardization of improved metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. Gastroenterology 2022; 163(5): 1407–1422
Nam H, Hong SS, Jung KH, Kang S, Park MS, Kang S, Kim HS, Mai VH, Kim J, Lee H, Lee W, Suh YJ, Lim JH, Kim SY, Kim SC, Kim SH, Park S. A serum marker for early pancreatic cancer with a possible link to diabetes. J Natl Cancer Inst 2022; 114(2): 228–234
Wolrab D, Jirásko R, Cífková E, Höring M, Mei D, Chocholoušková M, Peterka O, Idkowiak J, Hrnčiarová T, Kuchař L, Ahrends R, Brumarová R, Friedecký D, Vivo-Truyols G, Škrha P, Škrha J, Kučera R, Melichar B, Liebisch G, Burkhardt R, Wenk MR, Cazenave-Gassiot A, Karásek P, Novotný I, Greplová K, Hrstka R, Holčapek M. Lipidomic profiling of human serum enables detection of pancreatic cancer. Nat Commun 2022; 13(1): 124
Staal B, Liu Y, Barnett D, Hsueh P, He Z, Gao C, Partyka K, Hurd MW, Singhi AD, Drake RR, Huang Y, Maitra A, Brand RE, Haab BB. The sTRA plasma biomarker: blinded validation of improved accuracy over CA19-9 in pancreatic cancer diagnosis. Clin Cancer Res 2019; 25(9): 2745–2754
Debernardi S, O’Brien H, Algahmdi AS, Malats N, Stewart GD, Plješa-Ercegovac M, Costello E, Greenhalf W, Saad A, Roberts R, Ney A, Pereira SP, Kocher HM, Duffy S, Blyuss O, Crnogorac-Jurcevic T. A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: a case-control study. PLoS Med 2020; 17(12): e1003489
Nesteruk K, Levink IJM, de Vries E, Visser IJ, Peppelenbosch MP, Cahen DL, Fuhler GM, Bruno MJ. Extracellular vesicle-derived microRNAs in pancreatic juice as biomarkers for detection of pancreatic ductal adenocarcinoma. Pancreatology 2022; 22(5): 626–635
Kartal E, Schmidt TSB, Molina-Montes E, Rodríguez-Perales S, Wirbel J, Maistrenko OM, Akanni WA, Alashkar Alhamwe B, Alves RJ, Carrato A, Erasmus HP, Estudillo L, Finkelmeier F, Fullam A, Glazek AM, Gómez-Rubio P, Hercog R, Jung F, Kandels S, Kersting S, Langheinrich M, Márquez M, Molero X, Orakov A, Van Rossum T, Torres-Ruiz R, Telzerow A, Zych K; MAGIC Study investigators; PanGenEU Study investigators; Benes V, Zeller G, Trebicka J, Real FX, Malats N, Bork P. A faecal microbiota signature with high specificity for pancreatic cancer. Gut 2022; 71(7): 1359–1372
Kelly KN, Macedo FI, Merchant NB. Neoadjuvant therapy. Adv Surg 2020; 54: 49–68
Du Y, Ma Y, Zhu Q, Fu Y, Li Y, Zhang Y, Li M, Feng F, Yuan P, Wang X. GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma. Front Med 2023; 17(1): 119–131
Capula M, Perán M, Xu G, Donati V, Yee D, Gregori A, Assaraf YG, Giovannetti E, Deng D. Role of drug catabolism, modulation of oncogenic signaling and tumor microenvironment in microbe-mediated pancreatic cancer chemoresistance. Drug Resist Updat 2022; 64: 100864
Erkan M, Kleeff J, Gorbachevski A, Reiser C, Mitkus T, Esposito I, Giese T, Büchler MW, Giese NA, Friess H. Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 2007; 132(4): 1447–1464
Yu M, Tannock IF. Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer? Cancer Cell 2012; 21(3): 327–329
Chamma H, Vila IK, Taffoni C, Turtoi A, Laguette N. Activation of STING in the pancreatic tumor microenvironment: a novel therapeutic opportunity. Cancer Lett 2022; 538: 215694
Huang Y, Kanada M, Ye J, Deng Y, He Q, Lei Z, Chen Y, Li Y, Qin P, Zhang J, Wei J. Exosome-mediated remodeling of the tumor microenvironment: from local to distant intercellular communication. Cancer Lett 2022; 543: 215796
Starling N, Hawkes EA, Chau I, Watkins D, Thomas J, Webb J, Brown G, Thomas K, Barbachano Y, Oates J, Cunningham D. A dose escalation study of gemcitabine plus oxaliplatin in combination with imatinib for gemcitabine-refractory advanced pancreatic adenocarcinoma. Ann Oncol 2012; 23(4): 942–947
Hu C, Xia R, Zhang X, Li T, Ye Y, Li G, He R, Li Z, Lin Q, Zheng S, Chen R. circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis. Mol Cancer 2022; 21(1): 24
Malik S, Westcott JM, Brekken RA, Burrows FJ. CXCL12 in pancreatic cancer: its function and potential as a therapeutic drug target. Cancers (Basel) 2021; 14(1): 86
Wei L, Lin Q, Lu Y, Li G, Huang L, Fu Z, Chen R, Zhou Q. Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation. Cell Death Dis 2021; 12(4): 334
Zhang X, Zheng S, Hu C, Li G, Lin H, Xia R, Ye Y, He R, Li Z, Lin Q, Chen R, Zhou Q. Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair. Oncogene 2022; 41(16): 2372–2389
Guo Y, Wu H, Xiong J, Gou S, Cui J, Peng T. miR-222-3p-containing macrophage-derived extracellular vesicles confer gemcitabine resistance via TSC1-mediated mTOR/AKT/PI3K pathway in pancreatic cancer. Cell Biol Toxicol 2023; 39(4): 1203–1214
Halbrook CJ, Pontious C, Kovalenko I, Lapienyte L, Dreyer S, Lee HJ, Thurston G, Zhang Y, Lazarus J, Sajjakulnukit P, Hong HS, Kremer DM, Nelson BS, Kemp S, Zhang L, Chang D, Biankin A, Shi J, Frankel TL, Crawford HC, Morton JP, Pasca di Magliano M, Lyssiotis CA. Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab 2019; 29(6): 1390–1399.e6
Huanwen W, Zhiyong L, Xiaohua S, Xinyu R, Kai W, Tonghua L. Intrinsic chemoresistance to gemcitabine is associated with constitutive and laminin-induced phosphorylation of FAK in pancreatic cancer cell lines. Mol Cancer 2009; 8: 125
Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 2017; 36(13): 1770–1778
Richards KE, Xiao W, Hill R, On Behalf Of The Usc Pancreas Research Team. Cancer-associated fibroblasts confer gemcitabine resistance to pancreatic cancer cells through PTEN-targeting miRNAs in exosomes. Cancers (Basel) 2022; 14(11): 2812
Patel GK, Khan MA, Bhardwaj A, Srivastava SK, Zubair H, Patton MC, Singh S, Khushman M, Singh AP. Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and miR-155-mediated suppression of key gemcitabine-metabolising enzyme, DCK. Br J Cancer 2017; 116(5): 609–619
Chan MK, Chung JY, Tang PC, Chan AS, Ho JY, Lin TP, Chen J, Leung KT, To KF, Lan HY, Tang PM. TGF-β signaling networks in the tumor microenvironment. Cancer Lett 2022; 550: 215925
Cioffi M, Trabulo SM, Sanchez-Ripoll Y, Miranda-Lorenzo I, Lonardo E, Dorado J, Reis Vieira C, Ramirez JC, Hidalgo M, Aicher A, Hahn S, Sainz B Jr, Heeschen C. The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut 2015; 64(12): 1936–1948
Yang MC, Wang HC, Hou YC, Tung HL, Chiu TJ, Shan YS. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer 2015; 14(1): 179
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015; 527(7579): 525–530
Tang B, Yang Y, Kang M, Wang Y, Wang Y, Bi Y, He S, Shimamoto F. m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol Cancer 2020; 19(1): 3
Akada M, Crnogorac-Jurcevic T, Lattimore S, Mahon P, Lopes R, Sunamura M, Matsuno S, Lemoine NR. Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer. Clin Cancer Res 2005; 11(8): 3094–3101
Gu J, Huang W, Wang X, Zhang J, Tao T, Zheng Y, Liu S, Yang J, Chen ZS, Cai CY, Li J, Wang H, Fan Y. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol Cancer 2022; 21(1): 112
Zhou C, Yi C, Yi Y, Qin W, Yan Y, Dong X, Zhang X, Huang Y, Zhang R, Wei J, Ali DW, Michalak M, Chen XZ, Tang J. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes. Mol Cancer 2020; 19: 118
Xiong G, Liu C, Yang G, Feng M, Xu J, Zhao F, You L, Zhou L, Zheng L, Hu Y, Wang X, Zhang T, Zhao Y. Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer. J Hematol Oncol 2019; 12(1): 97
Chen ZW, Hu JF, Wang ZW, Liao CY, Kang FP, Lin CF, Huang Y, Huang L, Tian YF, Chen S. Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res 2022; 41(1): 153
Tu M, Li H, Lv N, Xi C, Lu Z, Wei J, Chen J, Guo F, Jiang K, Song G, Gao W, Miao Y. Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via Jun proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2. Mol Cancer 2017; 16(1): 66
Biliran H Jr, Wang Y, Banerjee S, Xu H, Heng H, Thakur A, Bollig A, Sarkar FH, Liao JD. Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line. Clin Cancer Res 2005; 11(16): 6075–6086
Melisi D, Xia Q, Paradiso G, Ling J, Moccia T, Carbone C, Budillon A, Abbruzzese JL, Chiao PJ. Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst 2011; 103(15): 1190–1204
Kadera BE, Toste PA, Wu N, Li L, Nguyen AH, Dawson DW, Donahue TR. Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition. Clin Cancer Res 2015; 21(1): 157–165
Wu L, Ge Y, Yuan Y, Li H, Sun H, Xu C, Wang Y, Zhao T, Wang X, Liu J, Gao S, Chang A, Hao J, Huang C. Genome-wide CRISPR screen identifies MTA3 as an inducer of gemcitabine resistance in pancreatic ductal adenocarcinoma. Cancer Lett 2022; 548: 215864
Safarzadeh Kozani P, Safarzadeh Kozani P, Rahbarizadeh F. CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success? Front Med 2022; 16(3): 322–338
Safarzadeh Kozani P, Safarzadeh Kozani P, Rahbarizadeh F. CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success? Front Med 2022; 16(3): 322–338
Yang K, Li J, Zhao L, Sun Z, Bai C. Estimating the number of Chinese cancer patients eligible for and benefit from immune checkpoint inhibitors. Front Med 2022; 16(5): 773–783
Xu R, Du S, Zhu J, Meng F, Liu B. Neoantigen-targeted TCR-T cell therapy for solid tumors: how far from clinical application. Cancer Lett 2022; 546: 215840
Bockorny B, Grossman JE, Hidalgo M. Facts and hopes in immunotherapy of pancreatic cancer. Clin Cancer Res 2022; 28(21): 4606–4617
Zhu YH, Zheng JH, Jia QY, Duan ZH, Yao HF, Yang J, Sun YW, Jiang SH, Liu DJ, Huo YM. Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment. Cell Oncol (Dordr) 2023; 46(1): 17–48
Ostios-Garcia L, Villamayor J, Garcia-Lorenzo E, Vinal D, Feliu J. Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer. World J Gastroenterol 2021; 27(40): 6775–6793
Chen TW, Hung WZ, Chiang SF, Chen WT, Ke TW, Liang JA, Huang CY, Yang PC, Huang KC, Chao KSC. Dual inhibition of TGFβ signaling and CSF1/CSF1R reprograms tumor-infiltrating macrophages and improves response to chemotherapy via suppressing PD-L1. Cancer Lett 2022; 543: 215795
Hadlandsmyth K, Conrad M, Steffensmeier KS, Van Tiem J, Obrecht A, Cullen JJ, Vander Weg MW. Enhancing the biopsychosocial approach to perioperative care: a pilot randomized trial of the perioperative pain self-management (PePS) intervention. Ann Surg 2022; 275(1): e8–e14
Wang H, Shao Q, Wang J, Zhao L, Wang L, Cheng Z, Yue C, Chen W, Wang H, Zhang Y. Decreased CXCR2 expression on circulating monocytes of colorectal cancer impairs recruitment and induces Re-education of tumor-associated macrophages. Cancer Lett 2022; 529: 112–125
Chen QY, Gao B, Tong D, Huang C. Crosstalk between extracellular vesicles and tumor-associated macrophage in the tumor microenvironment. Cancer Lett 2023; 552: 215979
Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012; 21(6): 836–847
Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F, Pasquali C, Calori G, Pessi F, Sperti C, Di Carlo V, Allavena P, Piemonti L. The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 2003; 63(21): 7451–7461
Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, Richman LP, Lin JH, Sun YH, Rech AJ, Balli D, Hay CA, Sela Y, Merrell AJ, Liudahl SM, Gordon N, Norgard RJ, Yuan S, Yu S, Chao T, Ye S, Eisinger-Mathason TSK, Faryabi RB, Tobias JW, Lowe SW, Coussens LM, Wherry EJ, Vonderheide RH, Stanger BZ. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 2018; 49(1): 178–193.e7
Zhang A, Qian Y, Ye Z, Chen H, Xie H, Zhou L, Shen Y, Zheng S. Cancer-associated fibroblasts promote M2 polarization of macrophages in pancreatic ductal adenocarcinoma. Cancer Med 2017; 6(2): 463–470
Yang X, Lin Y, Shi Y, Li B, Liu W, Yin W, Dang Y, Chu Y, Fan J, He R. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res 2016; 76(14): 4124–4135
Yu Y. Multi-target combinatory strategy to overcome tumor immune escape. Front Med 2022; 16(2): 208–215
Traub B, Link KH, Kornmann M. Curing pancreatic cancer. Semin Cancer Biol 2021; 76: 232–246
Hackert T, Sachsenmaier M, Hinz U, Schneider L, Michalski CW, Springfeld C, Strobel O, Jäger D, Ulrich A, Büchler MW. Locally advanced pancreatic cancer: neoadjuvant therapy with folfirinox results in resectability in 60% of the patients. Ann Surg 2016; 264(3): 457–463
Murphy JE, Wo JY, Ryan DP, Clark JW, Jiang W, Yeap BY, Drapek LC, Ly L, Baglini CV, Blaszkowsky LS, Ferrone CR, Parikh AR, Weekes CD, Nipp RD, Kwak EL, Allen JN, Corcoran RB, Ting DT, Faris JE, Zhu AX, Goyal L, Berger DL, Qadan M, Lillemoe KD, Talele N, Jain RK, DeLaney TF, Duda DG, Boucher Y, Fernández-Del Castillo C, Hong TS. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol 2019; 5(7): 1020–1027
Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, Faris JE, Zhu AX, Goyal L, Lillemoe KD, DeLaney TF, Fernández-Del Castillo C, Ferrone CR, Hong TS. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol 2018; 4(7): 963–969
Hackert T, Niesen W, Hinz U, Tjaden C, Strobel O, Ulrich A, Michalski CW, Büchler MW. Radical surgery of oligometastatic pancreatic cancer. Eur J Surg Oncol 2017; 43(2): 358–363
Tachezy M, Gebauer F, Janot M, Uhl W, Zerbi A, Montorsi M, Perinel J, Adham M, Dervenis C, Agalianos C, Malleo G, Maggino L, Stein A, Izbicki JR, Bockhorn M. Synchronous resections of hepatic oligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery 2016; 160(1): 136–144
Strobel O, Neoptolemos J, Jäger D, Büchler MW. Optimizing the outcomes of pancreatic cancer surgery. Nat Rev Clin Oncol 2019; 16(1): 11–26
Valle JW, Palmer D, Jackson R, Cox T, Neoptolemos JP, Ghaneh P, Rawcliffe CL, Bassi C, Stocken DD, Cunningham D, O’Reilly D, Goldstein D, Robinson BA, Karapetis C, Scarfe A, Lacaine F, Sand J, Izbicki JR, Mayerle J, Dervenis C, Oláh A, Butturini G, Lind PA, Middleton MR, Anthoney A, Sumpter K, Carter R, Büchler MW. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol 2014; 32(6): 504–512
Nassour I, Wang SC, Christie A, Augustine MM, Porembka MR, Yopp AC, Choti MA, Mansour JC, Xie XJ, Polanco PM, Minter RM. Minimally invasive versus open pancreaticoduodenectomy: a propensity-matched study from a national cohort of patients. Ann Surg 2018; 268(1): 151–157
Raoof M, Ituarte PHG, Woo Y, Warner SG, Singh G, Fong Y, Melstrom L. Propensity score-matched comparison of oncological outcomes between laparoscopic and open distal pancreatic resection. Br J Surg 2018; 105(5): 578–586
van Hilst J, de Rooij T, Klompmaker S, Rawashdeh M, Aleotti F, Al-Sarireh B, Alseidi A, Ateeb Z, Balzano G, Berrevoet F, Björnsson B, Boggi U, Busch OR, Butturini G, Casadei R, Del Chiaro M, Chikhladze S, Cipriani F, van Dam R, Damoli I, van Dieren S, Dokmak S, Edwin B, van Eijck C, Fabre JM, Falconi M, Farges O, Fernández-Cruz L, Forgione A, Frigerio I, Fuks D, Gavazzi F, Gayet B, Giardino A, Groot Koerkamp B, Hackert T, Hassenpflug M, Kabir I, Keck T, Khatkov I, Kusar M, Lombardo C, Marchegiani G, Marshall R, Menon KV, Montorsi M, Orville M, de Pastena M, Pietrabissa A, Poves I, Primrose J, Pugliese R, Ricci C, Roberts K, Røsok B, Sahakyan MA, Sánchez-Cabús S, Sandström P, Scovel L, Solaini L, Soonawalla Z, Souche FR, Sutcliffe RP, Tiberio GA, Tomazic A, Troisi R, Wellner U, White S, Wittel UA, Zerbi A, Bassi C, Besselink MG, Abu Hilal M; European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS). Minimally invasive versus open distal pancreatectomy for ductal adenocarcinoma (DIPLOMA): a pan-European propensity score matched study. Ann Surg 2019; 269(1): 10–17
Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, Cardin DB, Chiorean EG, Chung V, Czito B, Del Chiaro M, Dillhoff M, Donahue TR, Dotan E, Ferrone CR, Fountzilas C, Hardacre J, Hawkins WG, Klute K, Ko AH, Kunstman JW, LoConte N, Lowy AM, Moravek C, Nakakura EK, Narang AK, Obando J, Polanco PM, Reddy S, Reyngold M, Scaife C, Shen J, Vollmer C, Wolff RA, Wolpin BM, Lynn B, George GV. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19(4): 439–457
Zhang Y, Yang C, Cheng H, Fan Z, Huang Q, Lu Y, Fan K, Luo G, Jin K, Wang Z, Liu C, Yu X. Novel agents for pancreatic ductal adenocarcinoma: emerging therapeutics and future directions. J Hematol Oncol 2018; 11(1): 14
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321(5897): 1801–1806
Zhong J, Bai H, Wang Z, Duan J, Zhuang W, Wang D, Wan R, Xu J, Fei K, Ma Z, Zhang X, Wang J. Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions. Front Med 2023; 17(1): 18–42
Zhao H, Luo F, Xue J, Li S, Xu RH. Emerging immunological strategies: recent advances and future directions. Front Med 2021; 15(6): 805–828
Mi JQ, Xu J, Zhou J, Zhao W, Chen Z, Melenhorst JJ, Chen S. CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies. Front Med 2021; 15(6): 783–804
Chen S, Zhao W, Li J, Wu D; Lymphoid Disease Group, Chinese Society of Hematology, Chinese Medical Association. Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition). Front Med 2022; 16(5): 815–826
Bear AS, Vonderheide RH, O’Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell 2020; 38(6): 788–802
Li Y, Wang S, Lin M, Hou C, Li C, Li G. Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy. Front Med 2022; 16(3): 307–321
Heumann T, Judkins C, Li K, Lim SJ, Hoare J, Parkinson R, Cao H, Zhang T, Gai J, Celiker B, Zhu Q, McPhaul T, Durham J, Purtell K, Klein R, Laheru D, De Jesus-Acosta A, Le DT, Narang A, Anders R, Burkhart R, Burns W, Soares K, Wolfgang C, Thompson E, Jaffee E, Wang H, He J, Zheng L. A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. Nat Commun 2023; 14(1): 3650
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This research was supported by the National Natural Science Foundation of China (No. 82273452).
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Conflicts of interest Zhichen Jiang, Xiaohao Zheng, Min Li, and Mingyang Liu declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.
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Jiang, Z., Zheng, X., Li, M. et al. Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic challenges. Front. Med. 17, 1135–1169 (2023). https://doi.org/10.1007/s11684-023-1050-6
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DOI: https://doi.org/10.1007/s11684-023-1050-6