Skip to main content

Advertisement

SpringerLink
Log in

Pancreatic cancer epigenetics: adaptive metabolism reprograms starving primary tumors for widespread metastatic outgrowth

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Pancreatic cancer is a paradigm for adaptation to extreme stress. That is because genetic drivers are selected during tissue injury with epigenetic imprints encoding wound healing responses. Ironically, epigenetic memories of trauma that facilitate neoplasia can also recreate past stresses to restrain malignant progression through symbiotic tumor:stroma crosstalk. This is best exemplified by positive feedback between neoplastic chromatin outputs and fibroinflammatory stromal cues that encase malignant glands within a nutrient-deprived desmoplastic stroma. Because epigenetic imprints are chemically encoded by nutrient-derived metabolites bonded to chromatin, primary tumor metabolism adapts to preserve malignant epigenetic fidelity during starvation. Despite these adaptations, stromal stresses inevitably awaken primordial drives to seek more hospitable climates. The invasive migrations that ensue facilitate entry into the metastatic cascade. Metastatic routes present nutrient-replete reservoirs that accelerate malignant progression through adaptive metaboloepigenetics. This is best exemplified by positive feedback between biosynthetic enzymes and nutrient transporters that saturate malignant chromatin with pro-metastatic metabolite byproducts. Here we present a contemporary view of pancreatic cancer epigenetics: selection of neoplastic chromatin under fibroinflammatory pressures, preservation of malignant chromatin during starvation stresses, and saturation of metastatic chromatin by nutritional excesses that fuel lethal metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Schvartzman, J. M., Thompson, C. B., & Finley, L. W. S. (2018). Metabolic regulation of chromatin modifications and gene expression. Journal of Cell Biology, 217(7), 2247–2259. https://doi.org/10.1083/jcb.201803061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cavalli, G., & Heard, E. (2019). Advances in epigenetics link genetics to the environment and disease. Nature, 571(7766), 489–499. https://doi.org/10.1038/s41586-019-1411-0

    Article  CAS  PubMed  Google Scholar 

  3. Kinnaird, A., Zhao, S., Wellen, K. E., & Michelakis, E. D. (2016). Metabolic control of epigenetics in cancer. Nature Reviews Cancer, 16(11), 694–707. https://doi.org/10.1038/nrc.2016.82

    Article  CAS  PubMed  Google Scholar 

  4. Strahl, B. D., & Allis, C. D. (2000). The language of covalent histone modifications. Nature, 403(6765), 41–45. https://doi.org/10.1038/47412

    Article  CAS  PubMed  Google Scholar 

  5. Boon, R., Silveira, G. G., & Mostoslavsky, R. (2020). Nuclear metabolism and the regulation of the epigenome. Nature Metabolism, 2(11), 1190–1203. https://doi.org/10.1038/s42255-020-00285-4

    Article  CAS  PubMed  Google Scholar 

  6. Reid, M. A., Dai, Z., & Locasale, J. W. (2017). The impact of cellular metabolism on chromatin dynamics and epigenetics. Nature Cell Biology, 19(11), 1298–1306. https://doi.org/10.1038/ncb3629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ushijima, T., Clark, S. J., & Tan, P. (2021). Mapping genomic and epigenomic evolution in cancer ecosystems. Science, 373(6562), 1474–1479. https://doi.org/10.1126/science.abh1645

    Article  CAS  PubMed  Google Scholar 

  8. Locasale, J. W. (2018). New concepts in feedback regulation of glucose metabolism. Curr Opin Syst Biol, 8, 32–38. https://doi.org/10.1016/j.coisb.2017.11.005

    Article  PubMed  Google Scholar 

  9. Thompson, C. B., & Bielska, A. A. (2019). Growth factors stimulate anabolic metabolism by directing nutrient uptake. Journal of Biological Chemistry, 294(47), 17883–17888. https://doi.org/10.1074/jbc.AW119.008146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023). Pancreatic cancer: Advances and challenges. Cell, 186(8), 1729–1754. https://doi.org/10.1016/j.cell.2023.02.014

    Article  CAS  PubMed  Google Scholar 

  11. Encarnación-Rosado, J., & Kimmelman, A. C. (2021). Harnessing metabolic dependencies in pancreatic cancers. Nature Reviews. Gastroenterology & Hepatology, 18(7), 482–492. https://doi.org/10.1038/s41575-021-00431-7

    Article  Google Scholar 

  12. Halbrook, C. J., & Lyssiotis, C. A. (2017). Employing metabolism to improve the diagnosis and treatment of pancreatic cancer. Cancer Cell, 31(1), 5–19. https://doi.org/10.1016/j.ccell.2016.12.006

    Article  CAS  PubMed  Google Scholar 

  13. Rahib, L., Wehner, M. R., Matrisian, L. M., & Nead, K. T. (2021). Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open, 4(4), e214708. https://doi.org/10.1001/jamanetworkopen.2021.4708

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hayashi, A., Hong, J., & Iacobuzio-Donahue, C. A. (2021). The pancreatic cancer genome revisited. Nature Reviews. Gastroenterology & Hepatology, 18(7), 469–481. https://doi.org/10.1038/s41575-021-00463-z

    Article  Google Scholar 

  15. Sandgren, E. P., Luetteke, N. C., Palmiter, R. D., Brinster, R. L., & Lee, D. C. (1990). Overexpression of TGF alpha in transgenic mice: Induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell, 61(6), 1121–1135. https://doi.org/10.1016/0092-8674(90)90075-p

    Article  CAS  PubMed  Google Scholar 

  16. Halbrook, C. J., Wen, H. J., Ruggeri, J. M., Takeuchi, K. K., Zhang, Y., di Magliano, M. P., et al. (2017). Mitogen-activated protein kinase kinase activity maintains acinar-to-ductal metaplasia and is required for organ regeneration in pancreatitis. Cellular and Molecular Gastroenterology and Hepatology, 3(1), 99–118. https://doi.org/10.1016/j.jcmgh.2016.09.009

    Article  PubMed  Google Scholar 

  17. McDonald, O. G. (2022). The biology of pancreatic cancer morphology. Pathology, 54(2), 236–247. https://doi.org/10.1016/j.pathol.2021.09.012

    Article  CAS  PubMed  Google Scholar 

  18. Del Poggetto, E., Ho, I. L., Balestrieri, C., Yen, E. Y., Zhang, S., Citron, F., et al. (2021). Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis. Science, 373(6561), eabj0486. https://doi.org/10.1126/science.abj0486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alonso-Curbelo, D., Ho, Y. J., Burdziak, C., Maag, J. L. V., Morris, J. P. T., Chandwani, R., et al. (2021). A gene-environment-induced epigenetic program initiates tumorigenesis. Nature, 590(7847), 642–648. https://doi.org/10.1038/s41586-020-03147-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cobo, I., Martinelli, P., Flández, M., Bakiri, L., Zhang, M., Carrillo-de-Santa-Pau, E., et al. (2018). Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature, 554(7693), 533–537. https://doi.org/10.1038/nature25751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mallen-St Clair, J., Soydaner-Azeloglu, R., Lee, K. E., Taylor, L., Livanos, A., Pylayeva-Gupta, Y., et al. (2012). EZH2 couples pancreatic regeneration to neoplastic progression. Genes & Development, 26(5), 439–444. https://doi.org/10.1101/gad.181800.111

    Article  CAS  Google Scholar 

  22. Hill, W., Zaragkoulias, A., Salvador-Barbero, B., Parfitt, G. J., Alatsatianos, M., Padilha, A., et al. (2021). EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas. Current Biology, 31(12), 2550-2560.e2555. https://doi.org/10.1016/j.cub.2021.03.094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mathison, A. J., Kerketta, R., de Assuncao, T. M., Leverence, E., Zeighami, A., Urrutia, G., et al. (2021). Kras(G12D) induces changes in chromatin territories that differentially impact early nuclear reprogramming in pancreatic cells. Genome Biology, 22(1), 289. https://doi.org/10.1186/s13059-021-02498-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tape, C. J., Ling, S., Dimitriadi, M., McMahon, K. M., Worboys, J. D., Leong, H. S., et al. (2016). Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell, 165(4), 910–920. https://doi.org/10.1016/j.cell.2016.03.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Das, S., Shapiro, B., Vucic, E. A., Vogt, S., & Bar-Sagi, D. (2020). Tumor cell-derived IL1β promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Research, 80(5), 1088–1101. https://doi.org/10.1158/0008-5472.Can-19-2080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G., & Bar-Sagi, D. (2012). Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell, 21(6), 836–847. https://doi.org/10.1016/j.ccr.2012.04.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hruban, R. H., Goggins, M., Parsons, J., & Kern, S. E. (2000). Progression model for pancreatic cancer. Clinical Cancer Research, 6(8), 2969–2972.

    CAS  PubMed  Google Scholar 

  28. Notta, F., Chan-Seng-Yue, M., Lemire, M., Li, Y., Wilson, G. W., Connor, A. A., et al. (2016). A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature, 538(7625), 378–382. https://doi.org/10.1038/nature19823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tajan, M., Hock, A. K., Blagih, J., Robertson, N. A., Labuschagne, C. F., Kruiswijk, F., et al. (2018). A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metabolism, 28(5), 721-736.e726. https://doi.org/10.1016/j.cmet.2018.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Morris, J. P. T., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C. C., et al. (2019). α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature, 573(7775), 595–599. https://doi.org/10.1038/s41586-019-1577-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J. (2007). Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: Possible links between cell metabolism and stabilization of HIF. Journal of Biological Chemistry, 282(7), 4524–4532. https://doi.org/10.1074/jbc.M610415200

    Article  CAS  PubMed  Google Scholar 

  32. Zhu, J., Sammons, M. A., Donahue, G., Dou, Z., Vedadi, M., Getlik, M., et al. (2015). Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature, 525(7568), 206–211. https://doi.org/10.1038/nature15251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bachem, M. G., Schünemann, M., Ramadani, M., Siech, M., Beger, H., Buck, A., et al. (2005). Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology, 128(4), 907–921. https://doi.org/10.1053/j.gastro.2004.12.036

    Article  CAS  PubMed  Google Scholar 

  34. Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., et al. (2017). Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. Journal of Experimental Medicine, 214(3), 579–596. https://doi.org/10.1084/jem.20162024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tian, C., Clauser, K. R., Öhlund, D., Rickelt, S., Huang, Y., Gupta, M., et al. (2019). Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc Natl Acad Sci U S A, 116(39), 19609–19618. https://doi.org/10.1073/pnas.1908626116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Provenzano, P. P., Cuevas, C., Chang, A. E., Goel, V. K., Von Hoff, D. D., & Hingorani, S. R. (2012). Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 21(3), 418–429. https://doi.org/10.1016/j.ccr.2012.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lee, S. W., Zhang, Y., Jung, M., Cruz, N., Alas, B., & Commisso, C. (2019). EGFR-Pak signaling selectively regulates glutamine deprivation-induced macropinocytosis. Developmental Cell, 50(3), 381-392.e385. https://doi.org/10.1016/j.devcel.2019.05.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kamphorst, J. J., Nofal, M., Commisso, C., Hackett, S. R., Lu, W., Grabocka, E., et al. (2015). Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Research, 75(3), 544–553. https://doi.org/10.1158/0008-5472.Can-14-2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sullivan, M. R., Danai, L. V., Lewis, C. A., Chan, S. H., Gui, D. Y., Kunchok, T., et al. (2019). Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife, 8, e44235. https://doi.org/10.7554/eLife.44235

  40. Hollinshead, K. E. R., Parker, S. J., Eapen, V. V., Encarnacion-Rosado, J., Sohn, A., Oncu, T., et al. (2020). Respiratory supercomplexes promote mitochondrial efficiency and growth in severely hypoxic pancreatic cancer. Cell Rep, 33(1), 108231. https://doi.org/10.1016/j.celrep.2020.108231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kamphorst, J. J., Cross, J. R., Fan, J., de Stanchina, E., Mathew, R., White, E. P., et al. (2013). Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A, 110(22), 8882–8887. https://doi.org/10.1073/pnas.1307237110

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kerk, S. A., Papagiannakopoulos, T., Shah, Y. M., & Lyssiotis, C. A. (2021). Metabolic networks in mutant KRAS-driven tumours: Tissue specificities and the microenvironment. Nature Reviews Cancer, 21(8), 510–525. https://doi.org/10.1038/s41568-021-00375-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lo, E. K. W., Mears, B. M., Maurer, H. C., Idrizi, A., Hansen, K. D., Thompson, E. D., et al. (2023). Comprehensive DNA methylation analysis indicates that pancreatic intraepithelial neoplasia lesions are acinar-derived and epigenetically primed for carcinogenesis. Cancer Research. https://doi.org/10.1158/0008-5472.Can-22-4052

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lomberk, G., Dusetti, N., Iovanna, J., & Urrutia, R. (2019). Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine. Nature Communications, 10(1), 3875. https://doi.org/10.1038/s41467-019-11812-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Collisson, E. A., Bailey, P., Chang, D. K., & Biankin, A. V. (2019). Molecular subtypes of pancreatic cancer. Nature Reviews. Gastroenterology & Hepatology, 16(4), 207–220. https://doi.org/10.1038/s41575-019-0109-y

    Article  Google Scholar 

  46. Hayashi, A., Fan, J., Chen, R., Ho, Y.-J., Makohon-Moore, A. P., Lecomte, N., et al. (2020). A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nature Cancer, 1(1), 59–74. https://doi.org/10.1038/s43018-019-0010-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Noë, M., Hong, S. M., Wood, L. D., Thompson, E. D., Roberts, N. J., Goggins, M. G., et al. (2021). Pancreatic cancer pathology viewed in the light of evolution. Cancer and Metastasis Reviews. https://doi.org/10.1007/s10555-020-09953-z

    Article  PubMed  Google Scholar 

  48. Tu, M., Klein, L., Espinet, E., Georgomanolis, T., Wegwitz, F., Li, X., et al. (2021). TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer. Nat Cancer, 2(11), 1185–1203. https://doi.org/10.1038/s43018-021-00258-w

    Article  CAS  PubMed  Google Scholar 

  49. Somerville, T. D., Biffi, G., Daßler-Plenker, J., Hur, S. K., He, X. Y., Vance, K. E., et al. (2020). Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation. Elife, 9, e53381. https://doi.org/10.7554/eLife.53381

  50. Somerville, T. D. D., Xu, Y., Miyabayashi, K., Tiriac, H., Cleary, C. R., Maia-Silva, D., et al. (2018). TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Reports, 25(7), 1741-1755.e1747. https://doi.org/10.1016/j.celrep.2018.10.051

    Article  CAS  PubMed  Google Scholar 

  51. Lomberk, G., Blum, Y., Nicolle, R., Nair, A., Gaonkar, K. S., Marisa, L., et al. (2018). Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nature Communications, 9(1), 1978. https://doi.org/10.1038/s41467-018-04383-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, A. Y. L., Dubois, C. L., Sarai, K., Zarei, S., Schaeffer, D. F., Sander, M., et al. (2019). Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut, 68(3), 487–498. https://doi.org/10.1136/gutjnl-2017-314426

    Article  CAS  PubMed  Google Scholar 

  53. Brunton, H., Caligiuri, G., Cunningham, R., Upstill-Goddard, R., Bailey, U. M., Garner, I. M., et al. (2020). HNF4A and GATA6 loss reveals therapeutically actionable subtypes in pancreatic cancer. Cell Rep, 31(6), 107625. https://doi.org/10.1016/j.celrep.2020.107625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Flowers, B. M., Xu, H., Mulligan, A. S., Hanson, K. J., Seoane, J. A., Vogel, H., et al. (2021). Cell of origin influences pancreatic cancer subtype. Cancer Discovery, 11(3), 660–677. https://doi.org/10.1158/2159-8290.Cd-20-0633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Andricovich, J., Perkail, S., Kai, Y., Casasanta, N., Peng, W., & Tzatsos, A. (2018). Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell, 33(3), 512-526.e518. https://doi.org/10.1016/j.ccell.2018.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sherman, M. H., Yu, R. T., Tseng, T. W., Sousa, C. M., Liu, S., Truitt, M. L., et al. (2017). Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A, 114(5), 1129–1134. https://doi.org/10.1073/pnas.1620164114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Carrer, A., Trefely, S., Zhao, S., Campbell, S. L., Norgard, R. J., Schultz, K. C., et al. (2019). Acetyl-CoA metabolism supports multistep pancreatic tumorigenesis. Cancer Discovery, 9(3), 416–435. https://doi.org/10.1158/2159-8290.Cd-18-0567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bulusu, V., Tumanov, S., Michalopoulou, E., van den Broek, N. J., MacKay, G., Nixon, C., et al. (2017). Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Reports, 18(3), 647–658. https://doi.org/10.1016/j.celrep.2016.12.055

    Article  CAS  PubMed  Google Scholar 

  59. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F., & Kroemer, G. (2015). Acetyl coenzyme A: A central metabolite and second messenger. Cell Metabolism, 21(6), 805–821. https://doi.org/10.1016/j.cmet.2015.05.014

    Article  CAS  PubMed  Google Scholar 

  60. Shi, Y., Gao, W., Lytle, N. K., Huang, P., Yuan, X., Dann, A. M., et al. (2019). Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature, 569(7754), 131–135. https://doi.org/10.1038/s41586-019-1130-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V., & Benjamin, W. B. (2000). Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry, 39(5), 1169–1179. https://doi.org/10.1021/bi992159y

    Article  CAS  PubMed  Google Scholar 

  62. Wellen, K. E., Hatzivassiliou, G., Sachdeva, U. M., Bui, T. V., Cross, J. R., & Thompson, C. B. (2009). ATP-citrate lyase links cellular metabolism to histone acetylation. Science, 324(5930), 1076–1080. https://doi.org/10.1126/science.1164097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee, J. V., Carrer, A., Shah, S., Snyder, N. W., Wei, S., Venneti, S., et al. (2014). Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metabolism, 20(2), 306–319. https://doi.org/10.1016/j.cmet.2014.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao, S., Torres, A., Henry, R. A., Trefely, S., Wallace, M., Lee, J. V., et al. (2016). ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Reports, 17(4), 1037–1052. https://doi.org/10.1016/j.celrep.2016.09.069

    Article  CAS  PubMed  Google Scholar 

  65. Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., et al. (2012). Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell, 149(3), 656–670. https://doi.org/10.1016/j.cell.2012.01.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Amendola, C. R., Mahaffey, J. P., Parker, S. J., Ahearn, I. M., Chen, W. C., Zhou, M., et al. (2019). KRAS4A directly regulates hexokinase 1. Nature, 576(7787), 482–486. https://doi.org/10.1038/s41586-019-1832-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Son, J., Lyssiotis, C. A., Ying, H., Wang, X., Hua, S., Ligorio, M., et al. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 496(7443), 101–105. https://doi.org/10.1038/nature12040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M. H., Zhang, L., et al. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 536(7617), 479–483. https://doi.org/10.1038/nature19084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Commisso, C., Davidson, S. M., Soydaner-Azeloglu, R. G., Parker, S. J., Kamphorst, J. J., Hackett, S., et al. (2013). Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature, 497(7451), 633–637. https://doi.org/10.1038/nature12138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Olivares, O., Mayers, J. R., Gouirand, V., Torrence, M. E., Gicquel, T., Borge, L., et al. (2017). Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nature Communications, 8, 16031. https://doi.org/10.1038/ncomms16031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kim, P. K., Halbrook, C. J., Kerk, S. A., Radyk, M., Wisner, S., Kremer, D. M., et al. (2021). Hyaluronic acid fuels pancreatic cancer cell growth. Elife, 10, e62645. https://doi.org/10.7554/eLife.62645

  72. Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., et al. (2016). LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature, 539(7629), 390–395. https://doi.org/10.1038/nature20132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chini, C. C., Guerrico, A. M., Nin, V., Camacho-Pereira, J., Escande, C., Barbosa, M. T., et al. (2014). Targeting of NAD metabolism in pancreatic cancer cells: Potential novel therapy for pancreatic tumors. Clinical Cancer Research, 20(1), 120–130. https://doi.org/10.1158/1078-0432.Ccr-13-0150

    Article  CAS  PubMed  Google Scholar 

  74. Halbrook, C. J., Pontious, C., Kovalenko, I., Lapienyte, L., Dreyer, S., Lee, H. J., et al. (2019). Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metabolism, 29(6), 1390-1399.e1396. https://doi.org/10.1016/j.cmet.2019.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Badgley, M. A., Kremer, D. M., Maurer, H. C., DelGiorno, K. E., Lee, H. J., Purohit, V., et al. (2020). Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science, 368(6486), 85–89. https://doi.org/10.1126/science.aaw9872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mukhopadhyay, S., Biancur, D. E., Parker, S. J., Yamamoto, K., Banh, R. S., Paulo, J. A., et al. (2021). Autophagy is required for proper cysteine homeostasis in pancreatic cancer through regulation of SLC7A11. Proceedings of the National Academy of Sciences of the United States of America, 118(6), e2021475118. https://doi.org/10.1073/pnas.2021475118

  77. Santana-Codina, N., Roeth, A. A., Zhang, Y., Yang, A., Mashadova, O., Asara, J. M., et al. (2018). Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nature Communications, 9(1), 4945. https://doi.org/10.1038/s41467-018-07472-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Datta, R., Sivanand, S., Lau, A. N., Florek, L. V., Barbeau, A. M., Wyckoff, J., et al. (2022). Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors. Sci Adv, 8(3), eabg6383. https://doi.org/10.1126/sciadv.abg6383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Akakura, N., Kobayashi, M., Horiuchi, I., Suzuki, A., Wang, J., Chen, J., et al. (2001). Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Research, 61(17), 6548–6554.

    CAS  PubMed  Google Scholar 

  80. Schug, Z. T., Peck, B., Jones, D. T., Zhang, Q., Grosskurth, S., Alam, I. S., et al. (2015). Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell, 27(1), 57–71. https://doi.org/10.1016/j.ccell.2014.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Comerford, S. A., Huang, Z., Du, X., Wang, Y., Cai, L., Witkiewicz, A. K., et al. (2014). Acetate dependence of tumors. Cell, 159(7), 1591–1602. https://doi.org/10.1016/j.cell.2014.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mews, P., Donahue, G., Drake, A. M., Luczak, V., Abel, T., & Berger, S. L. (2017). Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature, 546(7658), 381–386. https://doi.org/10.1038/nature22405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Thienpont, B., Steinbacher, J., Zhao, H., D’Anna, F., Kuchnio, A., Ploumakis, A., et al. (2016). Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature, 537(7618), 63–68. https://doi.org/10.1038/nature19081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., et al. (2019). Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science, 363(6432), 1217–1222. https://doi.org/10.1126/science.aaw1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Laukka, T., Mariani, C. J., Ihantola, T., Cao, J. Z., Hokkanen, J., Kaelin, W. G., Jr., et al. (2016). Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. Journal of Biological Chemistry, 291(8), 4256–4265. https://doi.org/10.1074/jbc.M115.688762

    Article  CAS  PubMed  Google Scholar 

  86. Letouzé, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., et al. (2013). SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell, 23(6), 739–752. https://doi.org/10.1016/j.ccr.2013.04.018

    Article  CAS  PubMed  Google Scholar 

  87. Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., et al. (2012). Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes & Development, 26(12), 1326–1338. https://doi.org/10.1101/gad.191056.112

    Article  CAS  Google Scholar 

  88. Sciacovelli, M., Gonçalves, E., Johnson, T. I., Zecchini, V. R., da Costa, A. S., Gaude, E., et al. (2016). Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature, 537(7621), 544–547. https://doi.org/10.1038/nature19353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Batie, M., Frost, J., Frost, M., Wilson, J. W., Schofield, P., & Rocha, S. (2019). Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science, 363(6432), 1222–1226. https://doi.org/10.1126/science.aau5870

    Article  CAS  PubMed  Google Scholar 

  90. Fujikura, K., Alruwaii, Z. I., Haffner, M. C., Trujillo, M. A., Roberts, N. J., Hong, S. M., et al. (2021). Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis. The Journal of Pathology, 254(3), 279–288. https://doi.org/10.1002/path.5682

    Article  CAS  PubMed  Google Scholar 

  91. Oldham, W. M., Clish, C. B., Yang, Y., & Loscalzo, J. (2015). Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metabolism, 22(2), 291–303. https://doi.org/10.1016/j.cmet.2015.06.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Intlekofer, A. M., Dematteo, R. G., Venneti, S., Finley, L. W., Lu, C., Judkins, A. R., et al. (2015). Hypoxia induces production of L-2-hydroxyglutarate. Cell Metabolism, 22(2), 304–311. https://doi.org/10.1016/j.cmet.2015.06.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gupta, V. K., Sharma, N. S., Durden, B., Garrido, V. T., Kesh, K., Edwards, D., et al. (2021). Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer. Cancer Research, 81(15), 4001–4013. https://doi.org/10.1158/0008-5472.Can-20-2562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hayashi, A., Fan, J., Chen, R., Ho, Y. J., Makohon-Moore, A. P., Lecomte, N., et al. (2020). A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nat Cancer, 1(1), 59–74. https://doi.org/10.1038/s43018-019-0010-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Waddell, N., Pajic, M., Patch, A. M., Chang, D. K., Kassahn, K. S., Bailey, P., et al. (2015). Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518(7540), 495–501. https://doi.org/10.1038/nature14169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., et al. (1998). Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology, 153(3), 865–873. https://doi.org/10.1016/s0002-9440(10)65628-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Massagué, J., & Obenauf, A. C. (2016). Metastatic colonization by circulating tumour cells. Nature, 529(7586), 298–306. https://doi.org/10.1038/nature17038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., Jr., & Kinzler, K. W. (2013). Cancer genome landscapes. Science, 339(6127), 1546–1558. https://doi.org/10.1126/science.1235122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. García-Jiménez, C., & Goding, C. R. (2019). Starvation and pseudo-starvation as drivers of cancer metastasis through translation reprogramming. Cell Metabolism, 29(2), 254–267. https://doi.org/10.1016/j.cmet.2018.11.018

    Article  CAS  PubMed  Google Scholar 

  100. Whittle, M. C., Izeradjene, K., Rani, P. G., Feng, L., Carlson, M. A., DelGiorno, K. E., et al. (2015). RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell, 161(6), 1345–1360. https://doi.org/10.1016/j.cell.2015.04.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Halbrook, C. J., Thurston, G., Boyer, S., Anaraki, C., Jiménez, J. A., McCarthy, A., et al. (2022). Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells. Nat Cancer, 3(11), 1386–1403. https://doi.org/10.1038/s43018-022-00463-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Costa-Silva, B., Aiello, N. M., Ocean, A. J., Singh, S., Zhang, H., Thakur, B. K., et al. (2015). Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology, 17(6), 816–826. https://doi.org/10.1038/ncb3169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lee, J. W., Stone, M. L., Porrett, P. M., Thomas, S. K., Komar, C. A., Li, J. H., et al. (2019). Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature, 567(7747), 249–252. https://doi.org/10.1038/s41586-019-1004-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pommier, A., Anaparthy, N., Memos, N., Kelley, Z. L., Gouronnec, A., Yan, R., et al. (2018). Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science, 360(6394), eaao4908. https://doi.org/10.1126/science.aao4908

  105. Walter, P., & Ron, D. (2011). The unfolded protein response: From stress pathway to homeostatic regulation. Science, 334(6059), 1081–1086. https://doi.org/10.1126/science.1209038

    Article  CAS  PubMed  Google Scholar 

  106. Chiou, S. H., Risca, V. I., Wang, G. X., Yang, D., Grüner, B. M., Kathiria, A. S., et al. (2017). BLIMP1 induces transient metastatic heterogeneity in pancreatic cancer. Cancer Discovery, 7(10), 1184–1199. https://doi.org/10.1158/2159-8290.Cd-17-0250

    Article  PubMed  PubMed Central  Google Scholar 

  107. Chang, Q., Jurisica, I., Do, T., & Hedley, D. W. (2011). Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Research, 71(8), 3110–3120. https://doi.org/10.1158/0008-5472.Can-10-4049

    Article  CAS  PubMed  Google Scholar 

  108. Recouvreux, M. V., Moldenhauer, M. R., Galenkamp, K. M. O., Jung, M., James, B., Zhang, Y., et al. (2020). Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer. The Journal of Experimental Medicine, 217(9), e20200388. https://doi.org/10.1084/jem.20200388

  109. Jian, Z., Cheng, T., Zhang, Z., Raulefs, S., Shi, K., Steiger, K., et al. (2018). Glycemic variability promotes both local invasion and metastatic colonization by pancreatic ductal adenocarcinoma. Cellular and Molecular Gastroenterology and Hepatology, 6(4), 429–449. https://doi.org/10.1016/j.jcmgh.2018.07.003

    Article  PubMed  PubMed Central  Google Scholar 

  110. Dauer, P., Sharma, N. S., Gupta, V. K., Durden, B., Hadad, R., Banerjee, S., et al. (2019). ER stress sensor, glucose regulatory protein 78 (GRP78) regulates redox status in pancreatic cancer thereby maintaining “stemness.” Cell Death & Disease, 10(2), 132. https://doi.org/10.1038/s41419-019-1408-5

    Article  CAS  Google Scholar 

  111. Carstens, J. L., Yang, S., Correa de Sampaio, P., Zheng, X., Barua, S., McAndrews, K. M., et al. (2021). Stabilized epithelial phenotype of cancer cells in primary tumors leads to increased colonization of liver metastasis in pancreatic cancer. Cell Rep, 35(2), 108990. https://doi.org/10.1016/j.celrep.2021.108990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rhim, A. D., Mirek, E. T., Aiello, N. M., Maitra, A., Bailey, J. M., McAllister, F., et al. (2012). EMT and dissemination precede pancreatic tumor formation. Cell, 148(1–2), 349–361. https://doi.org/10.1016/j.cell.2011.11.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Simeonov, K. P., Byrns, C. N., Clark, M. L., Norgard, R. J., Martin, B., Stanger, B. Z., et al. (2021). Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states. Cancer Cell, 39(8), 1150-1162.e1159. https://doi.org/10.1016/j.ccell.2021.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Krauß, L., Urban, B. C., Hastreiter, S., Schneider, C., Wenzel, P., Hassan, Z., et al. (2022). HDAC2 facilitates pancreatic cancer metastasis. Cancer Research, 82(4), 695–707. https://doi.org/10.1158/0008-5472.Can-20-3209

    Article  PubMed  Google Scholar 

  115. Aiello, N. M., Maddipati, R., Norgard, R. J., Balli, D., Li, J., Yuan, S., et al. (2018). EMT subtype influences epithelial plasticity and mode of cell migration. Developmental Cell, 45(6), 681-695.e684. https://doi.org/10.1016/j.devcel.2018.05.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. McDonald, O. G., Wu, H., Timp, W., Doi, A., & Feinberg, A. P. (2011). Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nature Structural & Molecular Biology, 18(8), 867–874. https://doi.org/10.1038/nsmb.2084

    Article  CAS  Google Scholar 

  117. Yuan, S., Natesan, R., Sanchez-Rivera, F. J., Li, J., Bhanu, N. V., Yamazoe, T., et al. (2020). Global regulation of the histone mark H3K36me2 underlies epithelial plasticity and metastatic progression. Cancer Discovery, 10(6), 854–871. https://doi.org/10.1158/2159-8290.Cd-19-1299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jia, S., Noma, K., & Grewal, S. I. (2004). RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins. Science, 304(5679), 1971–1976. https://doi.org/10.1126/science.1099035

    Article  CAS  PubMed  Google Scholar 

  119. Tasdogan, A., Ubellacker, J. M., & Morrison, S. J. (2021). Redox regulation in cancer cells during metastasis. Cancer Discovery, 11(11), 2682–2692. https://doi.org/10.1158/2159-8290.Cd-21-0558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang, Y., Xu, Y., Lu, W., Li, J., Yu, S., Brown, E. J., et al. (2022). G6PD-mediated increase in de novo NADP(+) biosynthesis promotes antioxidant defense and tumor metastasis. Sci Adv, 8(29), eabo0404. https://doi.org/10.1126/sciadv.abo0404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bechard, M. E., Smalling, R., Hayashi, A., Zhong, Y., Word, A. E., Campbell, S. L., et al. (2020). Pancreatic cancers suppress negative feedback of glucose transport to reprogram chromatin for metastasis. Nature Communications, 11(1), 4055. https://doi.org/10.1038/s41467-020-17839-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Torphy, R. J., Wang, Z., True-Yasaki, A., Volmar, K. E., Rashid, N., Yeh, B., et al. (2018). Stromal content is correlated with tissue site, contrast retention, and survival in pancreatic adenocarcinoma. JCO Precision Oncology, 2018, PO.17.00121. https://doi.org/10.1200/po.17.00121

  123. Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., et al. (2010). Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature, 467(7319), 1114–1117. https://doi.org/10.1038/nature09515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Makohon-Moore, A. P., Zhang, M., Reiter, J. G., Bozic, I., Allen, B., Kundu, D., et al. (2017). Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nature Genetics, 49(3), 358–366. https://doi.org/10.1038/ng.3764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Maddipati, R., & Stanger, B. Z. (2015). Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discovery, 5(10), 1086–1097. https://doi.org/10.1158/2159-8290.Cd-15-0120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Iacobuzio-Donahue, C. A., Litchfield, K., & Swanton, C. (2020). Intratumor heterogeneity reflects clinical disease course. Nature Cancer, 1(1), 3–6. https://doi.org/10.1038/s43018-019-0002-1

    Article  PubMed  Google Scholar 

  127. McDonald, O. G., Li, X., Saunders, T., Tryggvadottir, R., Mentch, S. J., Warmoes, M. O., et al. (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nature Genetics, 49(3), 367–376. https://doi.org/10.1038/ng.3753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Roe, J. S., Hwang, C. I., Somerville, T. D. D., Milazzo, J. P., Lee, E. J., Da Silva, B., et al. (2017). Enhancer reprogramming promotes pancreatic cancer metastasis. Cell, 170(5), 875-888.e820. https://doi.org/10.1016/j.cell.2017.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Connor, A. A., Denroche, R. E., Jang, G. H., Lemire, M., Zhang, A., Chan-Seng-Yue, M., et al. (2019). Integration of genomic and transcriptional features in pancreatic cancer reveals increased cell cycle progression in metastases. Cancer Cell, 35(2), 267-282.e267. https://doi.org/10.1016/j.ccell.2018.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bechard, M. E., Word, A. E., Tran, A. V., Liu, X., Locasale, J. W., & McDonald, O. G. (2018). Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases. Oncogene, 37(38), 5248–5256. https://doi.org/10.1038/s41388-018-0346-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Smalling, R. V., Bechard, M. E., Duryea, J., Kingsley, P. J., Roberts, E. R., Marnett, L. J., et al. (2022). Aminopyridine analogs selectively target metastatic pancreatic cancer. Oncogene, 41(10), 1518–1525. https://doi.org/10.1038/s41388-022-02183-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Reiter, J. G., Makohon-Moore, A. P., Gerold, J. M., Heyde, A., Attiyeh, M. A., Kohutek, Z. A., et al. (2018). Minimal functional driver gene heterogeneity among untreated metastases. Science, 361(6406), 1033–1037. https://doi.org/10.1126/science.aat7171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jiang, H., Torphy, R. J., Steiger, K., Hongo, H., Ritchie, A. J., Kriegsmann, M., et al. (2020). Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. The Journal of Clinical Investigation, 130(9), 4704–4709. https://doi.org/10.1172/jci136760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bergers, G., & Fendt, S. M. (2021). The metabolism of cancer cells during metastasis. Nature Reviews Cancer, 21(3), 162–180. https://doi.org/10.1038/s41568-020-00320-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Iacobuzio-Donahue, C. A., Fu, B., Yachida, S., Luo, M., Abe, H., Henderson, C. M., et al. (2009). DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. Journal of Clinical Oncology, 27(11), 1806–1813. https://doi.org/10.1200/jco.2008.17.7188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A., et al. (2014). Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell, 25(6), 735–747. https://doi.org/10.1016/j.ccr.2014.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. McDonald, O. G. (2020). Cancer metastasis: Selectable traits without genetic constraints. Mol Cell Oncol, 7(6), 1825910. https://doi.org/10.1080/23723556.2020.1825910

    Article  PubMed  PubMed Central  Google Scholar 

  138. He, D., Feng, H., Sundberg, B., Yang, J., Powers, J., Christian, A. H., et al. (2022). Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis. Molecular Cell, 82(16), 3045-3060.e3011. https://doi.org/10.1016/j.molcel.2022.06.005

    Article  CAS  PubMed  Google Scholar 

  139. Salas, J. R., & Clark, P. M. (2022). Signaling pathways that drive (18)F-FDG accumulation in cancer. Journal of Nuclear Medicine, 63(5), 659–663. https://doi.org/10.2967/jnumed.121.262609

    Article  CAS  PubMed  Google Scholar 

  140. Ghergurovich, J. M., Esposito, M., Chen, Z., Wang, J. Z., Bhatt, V., Lan, T., et al. (2020). Glucose-6-phosphate dehydrogenase is not essential for K-Ras-driven tumor growth or metastasis. Cancer Research, 80(18), 3820–3829. https://doi.org/10.1158/0008-5472.Can-19-2486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shan, C., Elf, S., Ji, Q., Kang, H. B., Zhou, L., Hitosugi, T., et al. (2014). Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Molecular Cell, 55(4), 552–565. https://doi.org/10.1016/j.molcel.2014.06.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhang, Y., Xu, Y., Lu, W., Ghergurovich, J. M., Guo, L., Blair, I. A., et al. (2021). Upregulation of antioxidant capacity and nucleotide precursor availability suffices for oncogenic transformation. Cell Metabolism, 33(1), 94-109.e108. https://doi.org/10.1016/j.cmet.2020.10.002

    Article  CAS  PubMed  Google Scholar 

  143. Billin, A. N., Eilers, A. L., Coulter, K. L., Logan, J. S., & Ayer, D. E. (2000). MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a max-like network. Molecular and Cellular Biology, 20(23), 8845–8854. https://doi.org/10.1128/mcb.20.23.8845-8854.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Stoltzman, C. A., Peterson, C. W., Breen, K. T., Muoio, D. M., Billin, A. N., & Ayer, D. E. (2008). Glucose sensing by MondoA: Mlx complexes: A role for hexokinases and direct regulation of thioredoxin-interacting protein expression. Proc Natl Acad Sci U S A, 105(19), 6912–6917. https://doi.org/10.1073/pnas.0712199105

    Article  PubMed  PubMed Central  Google Scholar 

  145. Peterson, C. W., Stoltzman, C. A., Sighinolfi, M. P., Han, K. S., & Ayer, D. E. (2010). Glucose controls nuclear accumulation, promoter binding, and transcriptional activity of the MondoA-Mlx heterodimer. Molecular and Cellular Biology, 30(12), 2887–2895. https://doi.org/10.1128/mcb.01613-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Stoltzman, C. A., Kaadige, M. R., Peterson, C. W., & Ayer, D. E. (2011). MondoA senses non-glucose sugars: Regulation of thioredoxin-interacting protein (TXNIP) and the hexose transport curb. Journal of Biological Chemistry, 286(44), 38027–38034. https://doi.org/10.1074/jbc.M111.275503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wu, N., Zheng, B., Shaywitz, A., Dagon, Y., Tower, C., Bellinger, G., et al. (2013). AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Molecular Cell, 49(6), 1167–1175. https://doi.org/10.1016/j.molcel.2013.01.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7(1), 77–85. https://doi.org/10.1016/j.ccr.2004.11.022

    Article  CAS  PubMed  Google Scholar 

  149. Maddalena, M., Mallel, G., Nataraj, N. B., Shreberk-Shaked, M., Hassin, O., Mukherjee, S., et al. (2021). TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment. Proceedings of the National Academy of Sciences of the United States of America, 118(23), e2025631118. https://doi.org/10.1073/pnas.2025631118

  150. Siolas, D., Vucic, E., Kurz, E., Hajdu, C., & Bar-Sagi, D. (2021). Gain-of-function p53(R172H) mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy. Cell Rep, 36(8), 109578. https://doi.org/10.1016/j.celrep.2021.109578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Martin, T. D., Patel, R. S., Cook, D. R., Choi, M. Y., Patil, A., Liang, A. C., et al. (2021). The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science, 373(6561), 1327–1335. https://doi.org/10.1126/science.abg5784

    Article  CAS  PubMed  Google Scholar 

  152. Su, X., Wellen, K. E., & Rabinowitz, J. D. (2016). Metabolic control of methylation and acetylation. Current Opinion in Chemical Biology, 30, 52–60. https://doi.org/10.1016/j.cbpa.2015.10.030

    Article  CAS  PubMed  Google Scholar 

  153. Mentch, S. J., Mehrmohamadi, M., Huang, L., Liu, X., Gupta, D., Mattocks, D., et al. (2015). Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metabolism, 22(5), 861–873. https://doi.org/10.1016/j.cmet.2015.08.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yang, S., Wang, X., Contino, G., Liesa, M., Sahin, E., Ying, H., et al. (2011). Pancreatic cancers require autophagy for tumor growth. Genes & Development, 25(7), 717–729. https://doi.org/10.1101/gad.2016111

    Article  CAS  Google Scholar 

  155. Haws, S. A., Yu, D., Ye, C., Wille, C. K., Nguyen, L. C., Krautkramer, K. A., et al. (2020). Methyl-metabolite depletion elicits adaptive responses to support heterochromatin stability and epigenetic persistence. Molecular Cell, 78(2), 210-223.e218. https://doi.org/10.1016/j.molcel.2020.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ye, C., Sutter, B. M., Wang, Y., Kuang, Z., & Tu, B. P. (2017). A metabolic function for phospholipid and histone methylation. Molecular Cell, 66(2), 180-193.e188. https://doi.org/10.1016/j.molcel.2017.02.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tiwari, A., Tashiro, K., Dixit, A., Soni, A., Vogel, K., Hall, B., et al. (2020). Loss of HIF1A from pancreatic cancer cells increases expression of PPP1R1B and degradation of p53 to promote invasion and metastasis. Gastroenterology, 159(5), 1882-1897.e1885. https://doi.org/10.1053/j.gastro.2020.07.046

    Article  CAS  PubMed  Google Scholar 

  158. Sullivan, W. J., Mullen, P. J., Schmid, E. W., Flores, A., Momcilovic, M., Sharpley, M. S., et al. (2018). Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization. Cell, 175(1), 117-132.e121. https://doi.org/10.1016/j.cell.2018.08.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Wellen, K. E., & Snyder, N. W. (2019). Should we consider subcellular compartmentalization of metabolites, and if so, how do we measure them? Current Opinion in Clinical Nutrition and Metabolic Care, 22(5), 347–354. https://doi.org/10.1097/mco.0000000000000580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sivanand, S., Rhoades, S., Jiang, Q., Lee, J. V., Benci, J., Zhang, J., et al. (2017). Nuclear acetyl-CoA production by ACLY promotes homologous recombination. Molecular Cell, 67(2), 252-265.e256. https://doi.org/10.1016/j.molcel.2017.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Sulkowski, P. L., Oeck, S., Dow, J., Economos, N. G., Mirfakhraie, L., Liu, Y., et al. (2020). Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature, 582(7813), 586–591. https://doi.org/10.1038/s41586-020-2363-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Dougan, S. K. (2017). The pancreatic cancer microenvironment. Cancer Journal, 23(6), 321–325. https://doi.org/10.1097/ppo.0000000000000288

    Article  PubMed  Google Scholar 

  163. Li, N., Grivennikov, S. I., & Karin, M. (2011). The unholy trinity: Inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell, 19(4), 429–431. https://doi.org/10.1016/j.ccr.2011.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Whatcott, C. J., Diep, C. H., Jiang, P., Watanabe, A., LoBello, J., Sima, C., et al. (2015). Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clinical Cancer Research, 21(15), 3561–3568. https://doi.org/10.1158/1078-0432.Ccr-14-1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Aiello, N. M., Bajor, D. L., Norgard, R. J., Sahmoud, A., Bhagwat, N., Pham, M. N., et al. (2016). Metastatic progression is associated with dynamic changes in the local microenvironment. Nature Communications, 7, 12819. https://doi.org/10.1038/ncomms12819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Bhagat, T. D., Von Ahrens, D., Dawlaty, M., Zou, Y., Baddour, J., Achreja, A., et al. (2019). Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts. Elife, 8, e50663. https://doi.org/10.7554/eLife.50663.

  167. Schwörer, S., Vardhana, S. A., & Thompson, C. B. (2019). Cancer metabolism drives a stromal regenerative response. Cell Metabolism, 29(3), 576–591. https://doi.org/10.1016/j.cmet.2019.01.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Faubert, B., Solmonson, A., & DeBerardinis, R. J. (2020). Metabolic reprogramming and cancer progression. Science, 368(6487), https://doi.org/10.1126/science.aaw5473.

  169. Steele, C. W., Karim, S. A., Leach, J. D. G., Bailey, P., Upstill-Goddard, R., Rishi, L., et al. (2016). CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell, 29(6), 832–845. https://doi.org/10.1016/j.ccell.2016.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work is supported by National Institutes of Health grant R01 CA222594 (OGM).

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Rosenstiel Medical Sciences Building Room 4086A, Miami, FL, USA

    Arnaldo J. Franco Torres, Jeffrey Duryea & Oliver G. McDonald

  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Oliver G. McDonald

Authors
  1. Arnaldo J. Franco Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey Duryea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oliver G. McDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AJFT, JD, and OGM wrote the text and assembled the figures.

Corresponding author

Correspondence to Oliver G. McDonald.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torres, A.J.F., Duryea, J. & McDonald, O.G. Pancreatic cancer epigenetics: adaptive metabolism reprograms starving primary tumors for widespread metastatic outgrowth. Cancer Metastasis Rev 42, 389–407 (2023). https://doi.org/10.1007/s10555-023-10116-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-023-10116-z

Keywords

Search

Navigation