Skip to main content

MCT4 as a potential therapeutic target to augment gemcitabine chemosensitivity in resected pancreatic cancer

Abstract

Background

Pancreatic cancer is a devastating disease with a high relapse rate, even in case of resectable pancreatic cancer. Here, we aimed to identify the prognostic significance and therapeutic options of metabolic subtypes of resectable pancreatic cancer.

Method

Transcriptomic data were obtained from the TCGA-PAAD cohort in the The Cancer Genome Atlas (TCGA) data portal (n = 182). After integrative analysis of transcriptomic data in the discovery cohort, immunohistochemical (IHC) staining was performed in an independent cohort (n = 51) to validate the molecules of interest. Experimental testing for the molecules of interest was performed in vitro using pancreatic cancer cell line models AsPC1, BxPC3, MIA PaCa-2 and PANC-1.

Results

Two subtypes showing distinct gene expression patterns in the TCGA-PAAD dataset were identified. Of these, the active glucose metabolism subtype showed a significantly lower survival rate related to relapse after surgical resection. The genes SLC2A1 (GLUT1) and SLC16A3 (MCT4) were highly enriched in this subtype. The validation cohort showed a high MCT4 staining and a high relapse rate (p = 0.01). Several molecular pathways associated with aggressive tumor biology, including cell cycle regulation and Myc and mTOR downstream signaling, were highly enriched in the active glucose metabolism subtype, as well as with distinct responses to immunotherapy. MCT4 inhibition suppressed the in vitro malignant characteristics of pancreatic cancer cells and showed a synergistic effect with gemcitabine treatment.

Conclusions

From our data we conclude that MCT4 may serve as a potential therapeutic target in resectable pancreatic cancer. The precision medicine strategy for resectable pancreatic cancer should be validated in a clinical setting with a prospective study design.

This is a preview of subscription content, access via your institution.

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

Data availability

Transcriptome data used in this study are available via the The Cancer Genome Atlas (TCGA)-PAAD cohort (https://portal.gdc.cancer.gov/).

References

  1. 1.

    F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018)

    Article  Google Scholar 

  2. 2.

    A. Oba, C. Croce, P. Hosokawa, C. Meguid, R.J. Torphy, M.H. Al-Musawi, S. Ahrendt, A. Gleisner, R.D. Schulick, and M. Del Chiaro, Prognosis based definition of resectability in pancreatic cancer: a road map to new guidelines. Ann. Surg. (2020). https://doi.org/10.1097/SLA.0000000000003859 Online ahead of print.

    Article  PubMed  Google Scholar 

  3. 3.

    C.M. Kang, S.H. Lee, H.K. Hwang, M. Yun, W.J. Lee, Preoperative volume-based PET parameter, MTV2.5, as a potential surrogate marker for tumor biology and recurrence in resected pancreatic cancer. Medicine 95, 1–8 (2016)

    Article  Google Scholar 

  4. 4.

    S.H. Lee, H.K. Hwang, W.J. Lee, M. Yun, C.M. Kang, Preoperative metabolic tumor volume2.5 associated with early systemic metastasis in resected pancreatic cancer: a transcriptome-wide analysis. Gut Liver 13, 356–365 (2019)

    CAS  Article  Google Scholar 

  5. 5.

    Z. Ding, S. Zu, J. Gu, Evaluating the molecule-based prediction of clinical drug responses in cancer. Bioinformatics 32, 2891–2895 (2016)

    CAS  Article  Google Scholar 

  6. 6.

    G.H. Baek, Y.F. Tse, Z. Hu, D. Cox, N. Buboltz, P. McCue, C.J. Yeo, M.A. White, R.J. DeBerardinis, E.S. Knudsen, A.K. Witkiewicz, MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 9, 2233–2249 (2014)

    CAS  Article  Google Scholar 

  7. 7.

    A. Javaeed, S.K. Ghauri, MCT4 has a potential to be used as a prognostic biomarker - a systematic review and meta-analysis. Oncol. Rev. 13, 88–96 (2019)

    Article  Google Scholar 

  8. 8.

    T. Seufferlein, J. Mayerle, Pancreatic cancer in 2015: Precision medicine in pancreatic cancer-fact or fiction? Nat. Rev. Gastroenterol. Hepatol. 13, 74–75 (2016)

    CAS  Article  Google Scholar 

  9. 9.

    P. Jiang, S. Gu, D. Pan, J. Fu, A. Sahu, X. Hu, Z. Li, N. Traugh, X. Bu, B. Li, J. Liu, G.J. Freeman, M.A. Brown, K.W. Wucherpfennig, X.S. Liu, Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med. 24, 1550–1558 (2018)

    CAS  Article  Google Scholar 

  10. 10.

    J.P. Neoptolemos, J. Kleeff, P. Michl, E. Costello, W. Greenhalf, D.H. Palmer, Therapeutic developments in pancreatic cancer: current and future perspectives. Nat. Rev. Gastroenterol. Hepatol. 15, 333–348 (2018)

    Article  Google Scholar 

  11. 11.

    S. Lawrence, V. Adsay, G. Petersen, D. Klimstra, N. Bardeesy, M.D.M. Leiserson, R. Bowlby, K. Kasaian, I. Birol, K.L. Mungall, S. Sadeghi, J.N. Weinstein, P.T. Spellman,Y. Liu, L.T. Amundadottir, J. Tepper, A.D. Singhi, R. Dhir, D. Paul, T. Smyrk, L. Zhang,P. Kim, J. Bowen, J. Frick, J.M. Gastier-Foster, M. Gerken, K. Lau, K.M. Leraas, T.M. Lichtenberg, N.C. Ramirez, J. Renkel, M. Sherman, L. Wise, P. Yena, E. Zmuda, J. Shih, A. Ally, M. Balasundaram, R. Carlsen, A. Chu, E. Chuah, A. Clarke, N. Dhalla, R.A.Holt, S.J.M. Jones, D. Lee, Y. Ma, M.A. Marra, M. Mayo, R.A. Moore, A.J. Mungall, J.E. Schein, P. Sipahimalani, A. Tam, N. Thiessen, K. Tse, T. Wong, D. Brooks, J.T. Auman, S. Balu, T. Bodenheimer, D.N. Hayes, A.P. Hoyle, S.R. Jefferys, C.D. Jones, S. Meng, P.A. Mieczkowski, L.E. Mose, C.M. Perou, A.H. Perou, J. Roach, Y. Shi, J.V. Simons, T. Skelly, M.G. Soloway, D. Tan, U. Veluvolu, J.S. Parker, M.D. Wilkerson, A. Korkut, Y. Senbabaoglu,P. Burch, R. McWilliams, K. Chaffee, A. Oberg, W. Zhang, M.C. Gingras, D.A. Wheeler, L. Xi, M. Albert, J. Bartlett, H. Sekhon, Y. Stephen, Z. Howard, M. Judy, A. Breggia, R.T. Shroff, S. Chudamani, J. Liu, L. Lolla, R. Naresh, T. Pihl, Q. Sun, Y. Wan, Y. Wu, S. Jennifer, K. Roggin, K.F. Becker, M. Behera, J. Bennett, L. Boice, E. Burks, C.G. Carlotti Junior, J. Chabot, D. Pretti da Cunha Tirapelli, J. Sebastião dos Santos, M. Dubina, J. Eschbacher, M. Huang, L. Huelsenbeck-Dill, R. Jenkins, A. Karpov, R. Kemp, V. Lyadov, S. Maithel, G. Manikhas, E. Montgomery, H. Noushmehr, A. Osunkoya,T. Owonikoko, O. Paklina, O. Potapova, S. Ramalingam, W.K. Rathmell, K. Rieger-Christ, C. Saller, G. Setdikova, A. Shabunin, G. Sica, T. Su, T. Sullivan, P. Swanson, K. Tarvin, M. Tavobilov, L.B. Thorne, S. Urbanski, O. Voronina, T. Wang, D. Crain, E. Curley, J. Gardner, D. Mallery, S. Morris, J. Paulauskis, R. Penny, C. Shelton, T. Shelton, K.P. Janssen, O. Bathe, N. Bahary, J. Slotta-Huspenina, A. Johns, H. Hibshoosh, R.F. Hwang, A. Sepulveda, A. Radenbaugh, S.B. Baylin, M. Berrios, M.S. Bootwalla, A. Holbrook, P.H. Lai, D.T. Maglinte, S. Mahurkar, T.J. Triche, D.J. Van Den Berg, D.J. Weisenberger, L. Chin, R. Kucherlapati, M. Kucherlapati, A. Pantazi, P. Park, G. Saksena, D. Voet, P. Lin, S. Frazer, T. Defreitas, S. Meier, L. Chin, S.Y. Kwon, Y.H. Kim, S.J. Park, S.S. Han, S.H. Kim, H. Kim, E. Furth, M. Tempero, C. Sander, A. Biankin, D. Chang, P. Bailey, A. Gill, J. Kench, S. Grimmond, A. Johns, A.P. Cancer Genome Initiative (APGI, R. Postier, R. Zuna, H. Sicotte, J.A. Demchok, M.L. Ferguson, C.M. Hutter, K.R. Mills Shaw, M. Sheth, H.J. Sofia, R. Tarnuzzer, Z. Wang, L. Yang, J. (julia) Zhang, I. Felau, and J.C. Zenklusen, Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185-203 (2017)

  12. 12.

    S.B. Dreyer, M. Pinese, N.B. Jamieson, C.J. Scarlett, E.K. Colvin, M. Pajic, A.L. Johns, J.L. Humphris, J. Wu, M.J. Cowley, A. Chou, A.M. Nagrial, L. Chantrill, V.T. Chin, M.D. Jones, K. Moran-Jones, C.R. Carter, E.J. Dickson, J.S. Samra, N.D. Merrett, A.J. Gill, J.G. Kench, F. Duthie, D.K. Miller, S. Cooke, D. Aust, T. Knösel, P. Rümmele, R. Grützmann, C. Pilarsky, N.Q. Nguyen, E.A. Musgrove, P.J. Bailey, C.J. McKay, A.V. Biankin, D.K. Chang, Australian Pancreatic Cancer Genome Initiative, and Glasgow Precision Oncology Laboratory, precision oncology in surgery: patient selection for operable pancreatic cancer. Ann. Surg. 272, 366–376 (2020)

    Article  Google Scholar 

  13. 13.

    S.B. Dreyer, M. Pinese, N.B. Jamieson, C.J. Scarlett, E.K. Colvin, M. Pajic, A.L. Johns, J.L. Humphris, J. Wu, M.J. Cowley, A. Chou, A.M. Nagrial, L. Chantrill, V.T. Chin, M.D. Jones, K. Moran-Jones, C.R. Carter, E.J. Dickson, J.S. Samra, N.D. Merrett, A.J. Gill, J.G. Kench, F. Duthie, D.K. Miller, S. Cooke, D. Aust, T. Knösel, P. Rümmele, R. Grützmann, C. Pilarsky, N.Q. Nguyen, E.A. Musgrove, P.J. Bailey, C.J. McKay, A.V. Biankin, D.K. Chang, Australian Pancreatic Cancer Genome Initiative, and Glasgow Precision Oncology Laboratory, precision oncology in surgery: patient selection for operable pancreatic cancer. Ann. Surg. 1, 366–376 (2018)

    Google Scholar 

  14. 14.

    M.A. Tempero, D. Klimstra, J. Berlin, T. Hollingsworth, P. Kim, N. Merchant, M. Moore, D. Pleskow, A. Wang-Gillam, A.M. Lowy, Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer. Clin. Cancer Res. 19, 538–540 (2013)

    Article  Google Scholar 

  15. 15.

    H.K. Hwang, S.H. Lee, H.I. Kim, S.H. Kim, J. Choi, C.M. Kang, W.J. Lee, Yonsei criteria, a potential linkage to intratumoral Foxp3 + / CD8 + ratio for the prediction of oncologic outcomes in resected left-sided pancreatic cancer. Yonsei Med. J. 61, 291–300 (2020)

    CAS  Article  Google Scholar 

  16. 16.

    S.Y. Rho, M. Yun, C.M. Kang, S.H. Lee, H.K. Hwang, W.J. Lee, Different biological behaviors in left-sided pancreatic cancer according to Yonsei criteria: proposal of a modified Yonsei criteria score. Pancreatology 18, 990–995 (2018)

    Article  Google Scholar 

  17. 17.

    J.U. Chong, S.H. Kim, H.K. Hwang, C.M. Kang, W.J. Lee, Yonsei criteria: a clinical reflection of stage I left-sided pancreatic cancer. Oncotarget 8, 110830–110836 (2017)

    Article  Google Scholar 

  18. 18.

    S.H. Lee, H.K. Hwang, C.M. Kang, W.J. Lee, The Yonsei criteria as a clinically detectable parameter for excellent prognosis in resected left-sided pancreatic cancer: outcomes of a propensity score-matched analysis. Surg. Endosc. 31, 4656 (2017)

  19. 19.

    J.U. Chong, H.K. Hwang, J.H. Lee, M. Yun, C.M. Kang, W.J. Lee, Clinically determined type of 18F-fluoro-2-deoxyglucose uptake as an alternative prognostic marker in resectable pancreatic cancer. PLoS One 12, 1–15 (2017)

    Article  Google Scholar 

  20. 20.

    V.L. Payen, E. Mina, V.F. Van Hée, P.E. Porporato, P. Sonveaux, Monocarboxylate transporters in cancer. Mol. Metab. 33, 48–66 (2020)

    CAS  Article  Google Scholar 

  21. 21.

    K.J. Labori, M.H. Katz, C.W. Tzeng, B.A. Bjørnbeth, M. Cvancarova, B. Edwin, E.H. Kure, T.J. Eide, S. Dueland, T. Buanes, I.P. Glsadhaug, Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma - a population-based cohort study. Acta Oncol. 55, 265–277 (2016)

    CAS  Article  Google Scholar 

  22. 22.

    S. Yu, C. Zhang, K.P.K. Xie, Therapeutic resistance of pancreatic cancer: roadmap to its reversal. Biochim. Biophys. Acta (BBA) - Rev. Cancer 1875, 188461 (2020)

    Article  Google Scholar 

  23. 23.

    M. Sinn, M. Bahra, T. Liersch, K. Gellert, H. Messmann, W. Bechstein, D. Waldschmidt, L. Jacobasch, M. Wilhelm, B.M. Rau, R. Grützmann, A. Weinmann, G. Maschmeyer, U. Pelzer, J.M. Stieler, J.K. Striefler, M. Ghadimi, S. Bischoff, B. Dörken, H. Oettle, H. Riess, CONKO-005: adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after r0 resection of pancreatic cancer: a multicenter randomized phase III trial. J. Clin. Oncol. 35, 3330–3337 (2017)

    CAS  Article  Google Scholar 

  24. 24.

    K. Uesaka, N. Boku, A. Fukutomi, Y. Okamura, M. Konishi, I. Matsumoto, Y. Kaneoka, Y. Shimizu, S. Nakamori, H. Sakamoto, S. Morinaga, O. Kainuma, K. Imai, N. Sata, S. Hishinuma, H. Ojima, R. Yamaguchi, S. Hirano, T. Sudo, Y. Ohashi, Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388, 248–257 (2016)

    CAS  Article  Google Scholar 

  25. 25.

    Y. Hagiwara, Y. Ohashi, K. Uesaka, N. Boku, A. Fukutomi, Y. Okamura, M. Konishi, I. Matsumoto, Y. Kaneoka, Y. Shimizu, S. Nakamori, H. Sakamoto, S. Morinaga, O. Kainuma, K. Imai, N. Sata, S. Hishinuma, H. Ojima, R. Yamaguchi, S. Hirano, T. Sudo, Health-related quality of life of adjuvant chemotherapy with S-1 versus gemcitabine for resected pancreatic cancer: Results from a randomised phase III trial (JASPAC 01). Eur. J. Cancer 93, 79–88 (2018)

    CAS  Article  Google Scholar 

Download references

Funding

This study was supported by a faculty research grant from the Yonsei University College of Medicine (6-2015-0053).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Chang Moo Kang.

Ethics declarations

Conflict of interest

The authors declare that they have 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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, S.H., Hwang, H.K., Lee, W.J. et al. MCT4 as a potential therapeutic target to augment gemcitabine chemosensitivity in resected pancreatic cancer. Cell Oncol. (2021). https://doi.org/10.1007/s13402-021-00643-8

Download citation

Keywords

  • Pancreatic cancer
  • MCT4
  • Gemcitabine
  • Chemotherapy
  • Pancreatectomy