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Role of TGF-β in pancreatic ductal adenocarcinoma progression and PD-L1 expression

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Abstract

Purpose

The transforming growth factor-beta (TGF-β) pathway plays a paradoxical, context-dependent role in pancreatic ductal adenocarcinoma (PDAC): a tumor-suppressive role in non-metastatic PDAC and a tumor-promotive role in metastatic PDAC. We hypothesize that non-SMAD-TGF-β signaling induces PDAC progression.

Methods

We investigated the expression of non-SMAD-TGF-β signaling proteins (pMAPK14, PD-L1, pAkt and c-Myc) in patient-derived tissues, cell lines and an immunocompetent mouse model. Experimental models were complemented by comparing the signaling proteins in PDAC specimens from patients with various survival intervals. We manipulated models with TGF-β, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-β receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-κB, β-catenin, c-Myc and PD-L1 expression. PD-L1 expression was also investigated in cancer cells and tumor associated macrophages (TAMs) in a mouse model.

Results

We found that tumors from patients with aggressive PDAC had higher levels of the non-SMAD-TGF-β signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline β-catenin expression, TGF-β increased β-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-κB expression, but induced PD-L1 expression in some cancer models. In mice, gemcitabine plus galunisertib treatment decreased metastases (p = 0.018), whereas galunisertib increased PD-L1 expression (p < 0.0001). In the mice, liver metastases contained more TAMs compared to the primary pancreatic tumors (p = 0.001), and TGF-β increased TAM PD-L1 expression (p < 0.05).

Conclusions

In PDAC, the non-SMAD-TGF-β signaling pathway leads to more aggressive phenotypes, TAM-induced immunosuppression and PD-L1 expression. The divergent effects of TGF-β ligand versus receptor inhibition in tumor cells versus TAMs may explain the TGF-β paradox. Further evaluation of each mechanism is expected to lead to the development of targeted therapies.

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References

  1. R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019. CA Cancer J Clin 69, 7–34 (2019)

    PubMed  Google Scholar 

  2. The Cancer Genome Atlas Research Network, Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 e113 (2017)

  3. V.P. Balachandran, M. Luksza, J.N. Zhao, V. Makarov, J.A. Moral, R. Remark, B. Herbst, G. Askan, U. Bhanot, Y. Senbabaoglu, D.K. Wells, C.I.O. Cary, O. Grbovic-Huezo, M. Attiyeh, B. Medina, J. Zhang, J. Loo, J. Saglimbeni, M. Abu-Akeel, R. Zappasodi, N. Riaz, M. Smoragiewicz, Z.L. Kelley, O. Basturk, M. Gonen, A.J. Levine, P.J. Allen, D.T. Fearon, M. Merad, S. Gnjatic, C.A. Iacobuzio-Donahue, J.D. Wolchok, R.P. DeMatteo, T.A. Chan, B.D. Greenbaum, T. Merghoub, S.D. Leach, Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, 512–516 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. L. Danilova, W.J. Ho, Q.F. Zhu, T. Vithayathil, A. De Jesus-Acosta, N.S. Azad, D.A. Laheru, E.J. Fertig, R. Anders, E.M. Jaffee, M. Yarchoan, Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identify an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival. Cancer Immunol Res 7, 886–895 (2019)

  5. S.M. Hussain, L.F. Reed, B.A. Krasnick, G. Miranda-Carboni, R.C. Fields, Y. Bi, A. Elahi, A. Ajidahun, P.V. Dickson, J.L. Deneve, W.G. Hawkins, D. Shibata, E.S. Glazer, IL23 and TGF-β diminish macrophage associated metastasis in pancreatic carcinoma. Sci Rep 8, 5808 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  6. N.I. Medeiros, R.T. Mattos, C.A. Menezes, R.C.G. Fares, A. Talvani, W.O. Dutra, F. Rios-Santos, R. Correa-Oliveira, J.A.S. Gomes, IL-10 and TGF-beta unbalanced levels in neutrophils contribute to increase inflammatory cytokine expression in childhood obesity. Eur J Nutr 57, 2421–2430 (2017)

  7. E.S. Glazer, E. Welsh, J.M. Pimiento, J.K. Teer, M.P. Malafa, TGFbeta1 overexpression is associated with improved survival and low tumor cell proliferation in patients with early-stage pancreatic ductal adenocarcinoma. Oncotarget 8, 999–1006 (2017)

    Article  PubMed  Google Scholar 

  8. J. Gore, K.E. Craven, J.L. Wilson, G.A. Cote, M. Cheng, H.V. Nguyen, H.M. Cramer, S. Sherman, M. Korc, TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis. Oncotarget 6, 7504–7521 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  9. C.J. David, Y.H. Huang, M. Chen, J. Su, Y. Zou, N. Bardeesy, C.A. Iacobuzio-Donahue, J. Massague, TGF-beta tumor suppression through a lethal EMT. Cell 164, 1015–1030 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. L. Kubiczkova, L. Sedlarikova, R. Hajek, S. Sevcikova, TGF-beta - an excellent servant but a bad master. J Transl Med 10, 183 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. M. Javle, Y. Li, D. Tan, X. Dong, P. Chang, S. Kar, D. Li, Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PLoS One 9, e85942 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  12. C.-H. Heldin, A. Moustakas, Role of Smads in TGF beta signaling. Cell Tissue Res 347, 21–36 (2012)

    Article  CAS  PubMed  Google Scholar 

  13. H. Zhang, C. Liu, Y. Kong, H. Huang, C. Wang, H. Zhang, TGFbeta signaling in pancreatic ductal adenocarcinoma. Tumour Biol 36, 1613–1618 (2015)

    Article  CAS  PubMed  Google Scholar 

  14. X. Guo, X.F. Wang, Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 19, 71–88 (2009)

    Article  CAS  PubMed  Google Scholar 

  15. R. Nusse, H. Clevers, Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017)

    Article  CAS  PubMed  Google Scholar 

  16. A. Maier, A.L. Peille, V. Vuaroqueaux, M. Lahn, Anti-tumor activity of the TGF-beta receptor kinase inhibitor galunisertib (LY2157299 monohydrate) in patient-derived tumor xenografts. Cell Oncol 38, 131–144 (2015)

    Article  CAS  Google Scholar 

  17. J. Fuxe, M.C. Karlsson, TGF-beta-induced epithelial-mesenchymal transition: A link between cancer and inflammation. Semin Cancer Biol 22, 455–461 (2012)

    Article  CAS  PubMed  Google Scholar 

  18. L. Yu, M.C. Hebert, Y.E. Zhang, TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 21, 3749–3759 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. T.C. He, A.B. Sparks, C. Rago, H. Hermeking, L. Zawel, L.T. da Costa, P.J. Morin, B. Vogelstein, K.W. Kinzler, Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998)

    Article  CAS  PubMed  Google Scholar 

  20. D.R. Principe, J.A. Doll, J. Bauer, B. Jung, H.G. Munshi, L. Bartholin, B. Pasche, C. Lee, P.J. Grippo, TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst 106, djt369 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  21. T. Valenta, G. Hausmann, K. Basler, The many faces and functions of beta-catenin. EMBO J 31, 2714–2736 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. B. Ma, M.O. Hottiger, Crosstalk between Wnt/beta-catenin and NF-kappaB signaling pathway during inflammation. Front Immunol 7, 378 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  23. R. Batlle, E. Andres, L. Gonzalez, E. Llonch, A. Igea, N. Gutierrez-Prat, A. Berenguer-Llergo, A.R. Nebreda, Regulation of tumor angiogenesis and mesenchymal-endothelial transition by p38alpha through TGF-beta and JNK signaling. Nat Commun 10, 3071 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  24. D. Che, S. Zhang, Z. Jing, L. Shang, S. Jin, F. Liu, J. Shen, Y. Li, J. Hu, Q. Meng, Y. Yu, Macrophages induce EMT to promote invasion of lung cancer cells through the IL-6-mediated COX-2/PGE2/beta-catenin signalling pathway. Mol Immunol 90, 197–210 (2017)

    Article  CAS  PubMed  Google Scholar 

  25. A.K. Bonde, V. Tischler, S. Kumar, A. Soltermann, R.A. Schwendener, Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. D.A. Stewart, Y. Yang, L. Makowski, M.A. Troester, Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages. Mol Cancer Res 10, 727–738 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. E. Lengyel, L. Makowski, J. DiGiovanni, M.G. Kolonin, Cancer as a matter of fat: The crosstalk between adipose tissue and tumors. Trends Cancer 4, 374–384 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. A. Mantovani, S. Sozzani, M. Locati, P. Allavena, A. Sica, Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23, 549–555 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. A.J. Cozzo, A.M. Fuller, L. Makowski, Contribution of adipose tissue to development of cancer. Compr Physiol 8, 237–282 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  30. T.F. Gajewski, L. Corrales, J. Williams, B. Horton, A. Sivan, S. Spranger, Cancer immunotherapy targets based on understanding the T cell-inflamed versus non-T cell-inflamed tumor microenvironment. Adv Exp Med Biol 1036, 19–31 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Y.K. Huang, M. Wang, Y. Sun, N. Di Costanzo, C. Mitchell, A. Achuthan, J.A. Hamilton, R.A. Busuttil, A. Boussioutas, Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry. Nat Commun 10, 3928 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  32. M.F. Cuccarese, J.M. Dubach, C. Pfirschke, C. Engblom, C. Garris, M.A. Miller, M.J. Pittet, R. Weissleder, Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging. Nat Commun 8, 14293 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Y. Chen, H. Wen, C. Zhou, Q. Su, Y. Lin, Y. Xie, Y. Huang, Q. Qiu, J. Lin, X. Huang, W. Tan, C. Min, C. Wang, TNF-alpha derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/beta-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res 378, 41–50 (2019)

    Article  CAS  PubMed  Google Scholar 

  34. W.C. Huang, M.L. Chan, M.J. Chen, T.H. Tsai, Y.J. Chen, Modulation of macrophage polarization and lung cancer cell stemness by MUC1 and development of a related small-molecule inhibitor pterostilbene. Oncotarget 7, 39363–39375 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  35. J.H. Kim, S.Y. Park, Y. Jun, J.Y. Kim, J.S. Nam, Roles of Wnt target genes in the journey of cancer stem cells. Int J Mol Sci 18, 1604 (2017)

  36. J.M. Hsu, W. Xia, Y.H. Hsu, L.C. Chan, W.H. Yu, J.H. Cha, C.T. Chen, H.W. Liao, C.W. Kuo, K.H. Khoo, J.L. Hsu, C.W. Li, S.O. Lim, S.S. Chang, Y.C. Chen, G.X. Ren, M.C. Hung, STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun 9, 1908 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  37. Y. Osawa, E. Kojika, K. Nishikawa, M. Kimura, S. Osakaya, H. Miyauchi, T. Kanto, Y. Kawakami, K. Kimura, Programmed cell death ligand 1 (PD-L1) blockade attenuates metastatic colon cancer growth in cAMP-response element-binding protein (CREB)-binding protein (CBP)/beta-catenin inhibitor-treated livers. Oncotarget 10, 3013–3026 (2019)

    Article  PubMed  PubMed Central  Google Scholar 

  38. S. Spranger, R. Bao, T.F. Gajewski, Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015)

    Article  CAS  PubMed  Google Scholar 

  39. A. Pant, I.I. Lee, Z. Lu, B.R. Rueda, J. Schink, J.J. Kim, Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin. PLoS One 7, e41593 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. B. Sipos, S. Moser, H. Kalthoff, V. Torok, M. Lohr, G. Kloppel, A comprehensive characterization of pancreatic ductal carcinoma cell lines: Towards the establishment of an in vitro research platform. Virchows Arch 442, 444–452 (2003)

    Article  PubMed  Google Scholar 

  41. H. Jiang, S. Hegde, B.L. Knolhoff, Y. Zhu, J.M. Herndon, M.A. Meyer, T.M. Nywening, W.G. Hawkins, I.M. Shapiro, D.T. Weaver, J.A. Pachter, A. Wang-Gillam, D.G. DeNardo, Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22, 851–860 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. A. Zhang, J. Lakshmanan, A. Motameni, B.G. Harbrecht, MicroRNA-203 suppresses proliferation in liver cancer associated with PIK3CA, p38 MAPK, c-Jun, and GSK3 signaling. Mol Cell Biochem 441, 89–98 (2018)

    Article  CAS  PubMed  Google Scholar 

  43. C.N. Koyani, K. Kitz, C. Rossmann, E. Bernhart, E. Huber, C. Trummer, W. Windischhofer, W. Sattler, E. Malle, Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death. Biochem Pharmacol 104, 29–41 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. N. Thakur, S.K. Gudey, A. Marcusson, J.Y. Fu, A. Bergh, C.H. Heldin, M. Landstrom, TGFbeta-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1. Cell Cycle 13, 2400–2414 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. A.C. Ronda, A. Vasconsuelo, R. Boland, Extracellular-regulated kinase and p38 mitogen-activated protein kinases are involved in the antiapoptotic action of 17beta-estradiol in skeletal muscle cells. J Endocrinol 206, 235–246 (2010)

    Article  CAS  PubMed  Google Scholar 

  46. A. Gal, T. Sjoblom, L. Fedorova, S. Imreh, H. Beug, A. Moustakas, Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene 27, 1218–1230 (2008)

    Article  CAS  PubMed  Google Scholar 

  47. Q. Du, D.A. Geller, Cross-regulation between Wnt and NF-kappaB signaling pathways. For Immunopathol Dis Therap 1, 155–181 (2010)

    PubMed  PubMed Central  Google Scholar 

  48. B. Ma, M. Fey, M.O. Hottiger, WNT/beta-catenin signaling inhibits CBP-mediated RelA acetylation and expression of proinflammatory NF-kappaB target genes. J Cell Sci 128, 2430–2436 (2015)

    CAS  PubMed  Google Scholar 

  49. A. Busca, M. Saxena, S. Iqbal, J. Angel, A. Kumar, PI3K/Akt regulates survival during differentiation of human macrophages by maintaining NF-kappaB-dependent expression of antiapoptotic Bcl-xL. J Leukoc Biol 96, 1011–1022 (2014)

    Article  PubMed  Google Scholar 

  50. Y. Wang, Z. Lin, L. Sun, S. Fan, Z. Huang, D. Zhang, Z. Yang, J. Li, W. Chen, Akt/Ezrin Tyr353/NF-kappaB pathway regulates EGF-induced EMT and metastasis in tongue squamous cell carcinoma. Br J Cancer 110, 695–705 (2014)

    Article  CAS  PubMed  Google Scholar 

  51. J. Zhang, J.R. Shemezis, E.R. McQuinn, J. Wang, M. Sverdlov, A. Chenn, AKT activation by N-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development. Neural Dev 8, 7 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. E.L. Deer, J. Gonzalez-Hernandez, J.D. Coursen, J.E. Shea, J. Ngatia, C.L. Scaife, M.A. Firpo, S.J. Mulvihill, Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39, 425–435 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. C.H. Heldin, M. Landstrom, A. Moustakas, Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol 21, 166–176 (2009)

    Article  CAS  PubMed  Google Scholar 

  54. J.M. Yingling, W.T. McMillen, L. Yan, H. Huang, J.S. Sawyer, J. Graff, D.K. Clawson, K.S. Britt, B.D. Anderson, D.W. Beight, D. Desaiah, M.M. Lahn, K.A. Benhadji, M.J. Lallena, R.B. Holmgaard, X. Xu, F. Zhang, J.R. Manro, P.W. Iversen, C.V. Iyer, R.A. Brekken, M.D. Kalos, K.E. Driscoll, Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-beta receptor type I inhibitor. Oncotarget 9, 6659–6677 (2018)

    Article  PubMed  Google Scholar 

  55. S.C. Wang, I. Nassour, S. Xiao, S. Zhang, X. Luo, J. Lee, L. Li, X. Sun, L.H. Nguyen, J.C. Chuang, L. Peng, S. Daigle, J. Shen, H. Zhu, SWI/SNF component ARID1A restrains pancreatic neoplasia formation. Gut 68, 1259–1270 (2019)

  56. M. Wirth, S. Mahboobi, O.H. Kramer, G. Schneider, Concepts to target MYC in pancreatic Cancer. Mol Cancer Ther 15, 1792–1798 (2016)

    Article  CAS  PubMed  Google Scholar 

  57. T.K. Hayes, N.F. Neel, C. Hu, P. Gautam, M. Chenard, B. Long, M. Aziz, M. Kassner, K.L. Bryant, M. Pierobon, R. Marayati, S. Kher, S.D. George, M. Xu, A. Wang-Gillam, A.A. Samatar, A. Maitra, K. Wennerberg, E.F. Petricoin 3rd, H.H. Yin, B. Nelkin, A.D. Cox, J.J. Yeh, C.J. Der, Long-term ERK inhibition in KRAS-mutant pancreatic Cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell 29, 75–89 (2016)

    Article  CAS  PubMed  Google Scholar 

  58. J. Xu, Y. Chen, D. Huo, A. Khramtsov, G. Khramtsova, C. Zhang, K.H. Goss, O.I. Olopade, beta-catenin regulates c-Myc and CDKN1A expression in breast cancer cells. Mol Carcinog 55, 431–439 (2016)

    Article  PubMed  Google Scholar 

  59. J. Massague, TGFbeta signalling in context. Nat Rev Mol Cell Biol 13, 616–630 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. C. Mota Reyes, S. Teller, A. Muckenhuber, B. Konukiewitz, O. Safak, W. Weichert, H. Friess, G.O. Ceyhan, I.E. Demir, Neoadjuvant therapy remodels the pancreatic Cancer microenvironment via depletion of Protumorigenic immune cells. Clin Cancer Res 26, 220–231 (2020)

    Article  PubMed  Google Scholar 

  61. M. Ikeda, H. Takahashi, S. Kondo, M.M.F. Lahn, K. Ogasawara, K.A. Benhadji, H. Fujii, H. Ueno, Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Cancer Chemother Pharmacol 79, 1169–1177 (2017)

    Article  CAS  PubMed  Google Scholar 

  62. D. Melisi, R. Garcia-Carbonero, T. Macarulla, D. Pezet, G. Deplanque, M. Fuchs, J. Trojan, H. Oettle, M. Kozloff, A. Cleverly, C. Smith, S.T. Estrem, I. Gueorguieva, M.M.F. Lahn, A. Blunt, K.A. Benhadji, J. Tabernero, Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer 119, 1208–1214 (2018)

  63. G. Sannino, N. Armbruster, M. Bodenhofer, U. Haerle, D. Behrens, M. Buchholz, U. Rothbauer, B. Sipos, C. Schmees, Role of BCL9L in transforming growth factor-beta (TGF-beta)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer. Oncotarget 7, 73725–73738 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  64. A.M. Saad, T. Turk, M.J. Al-Husseini, O. Abdel-Rahman, Trends in pancreatic adenocarcinoma incidence and mortality in the United States in the last four decades; a SEER-based study. BMC Cancer 18, 688 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  65. Y. Fujiwara, H. Nokihara, Y. Yamada, N. Yamamoto, K. Sunami, H. Utsumi, H. Asou, O.I. Takahash, K. Ogasawara, I. Gueorguieva, T. Tamura, Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 76, 1143–1152 (2015)

    Article  CAS  PubMed  Google Scholar 

  66. S. Tanaka, Molecular pathogenesis and targeted therapy of pancreatic Cancer. Ann Surg Oncol 23(Suppl 2), S197–S205 (2016)

    Article  PubMed  Google Scholar 

  67. M.D. Ferguson, L. Dong, J. Wan, J.L. Deneve, P.V. Dickson, S.W. Behrman, D. Shibata, M.G. Martin, E.S. Glazer, Molecular alterations associated with DNA repair in pancreatic adenocarcinoma are associated with sites of recurrence. J Gastrointest Cancer 50, 285–291 (2018)

  68. S. Ebrahimi, M. Hosseini, S. Shahidsales, M. Maftouh, G.A. Ferns, M. Ghayour-Mobarhan, S.M. Hassanian, A. Avan, Targeting the Akt/PI3K signaling pathway as a potential therapeutic strategy for the treatment of pancreatic Cancer. Curr Med Chem 24, 1321–1331 (2017)

    Article  CAS  PubMed  Google Scholar 

  69. T.A. Yap, L. Yan, A. Patnaik, I. Fearen, D. Olmos, K. Papadopoulos, R.D. Baird, L. Delgado, A. Taylor, L. Lupinacci, R. Riisnaes, L.L. Pope, S.P. Heaton, G. Thomas, M.D. Garrett, D.M. Sullivan, J.S. de Bono, A.W. Tolcher, First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29, 4688–4695 (2011)

    Article  CAS  PubMed  Google Scholar 

  70. V. Chung, S. McDonough, P.A. Philip, D. Cardin, A. Wang-Gillam, L. Hui, M.A. Tejani, T.E. Seery, I.A. Dy, T. Al Baghdadi, A.E. Hendifar, L.A. Doyle, A.M. Lowy, K.A. Guthrie, C.D. Blanke, H.S. Hochster, Effect of Selumetinib and MK-2206 vs Oxaliplatin and fluorouracil in patients with metastatic pancreatic Cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol 3, 516–522 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  71. J. Hutcheson, U. Balaji, M.R. Porembka, M.B. Wachsmann, P.A. McCue, E.S. Knudsen, A.K. Witkiewicz, Immunologic and metabolic features of pancreatic ductal adenocarcinoma define prognostic subtypes of disease. Clin Cancer Res 22, 3606–3617 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. M. Masetti, G. Acquaviva, M. Visani, G. Tallini, A. Fornelli, M. Ragazzi, F. Vasuri, D. Grifoni, S. Di Giacomo, S. Fiorino, R. Lombardi, D. Tuminati, M. Ravaioli, C. Fabbri, M.L. Bacchi-Reggiani, A. Pession, E. Jovine, D. de Biase, Long-term survivors of pancreatic adenocarcinoma show low rates of genetic alterations in KRAS, TP53 and SMAD4. Cancer Biomark 21, 323–334 (2018)

    Article  CAS  PubMed  Google Scholar 

  73. J.Z. Xu, W.Q. Wang, W.H. Zhang, H.X. Xu, H.L. Gao, S.R. Zhang, C.T. Wu, S. Li, H. Li, J. Xu, X.J. Yu, L. Liu, The loss of SMAD4/DPC4 expression associated with a strongly activated hedgehog signaling pathway predicts poor prognosis in resected pancreatic Cancer. J Cancer 10, 4123–4131 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. A.F. Hezel, V. Deshpande, S.M. Zimmerman, G. Contino, B. Alagesan, M.R. O'Dell, L.B. Rivera, J. Harper, S. Lonning, R.A. Brekken, N. Bardeesy, TGF-beta and alphavbeta6 integrin act in a common pathway to suppress pancreatic cancer progression. Cancer Res 72, 4840–4845 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. R.J. Akhurst, A. Hata, Targeting the TGF beta signalling pathway in disease. Nat Rev Drug Discov 11, 790–811 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. G. Wang, Y. Yu, C. Sun, T. Liu, T. Liang, L. Zhan, X. Lin, X.H. Feng, STAT3 selectively interacts with Smad3 to antagonize TGF-beta. Oncogene 35, 4388–4398 (2016)

    Article  CAS  PubMed  Google Scholar 

  77. X. Xiao, S. Fischbach, T. Zhang, C. Chen, Q. Sheng, R. Zimmerman, S. Patnaik, J. Fusco, Y. Ming, P. Guo, C. Shiota, K. Prasadan, N. Gangopadhyay, S.Z. Husain, H. Dong, G.K. Gittes, SMAD3/Stat3 signaling mediates beta-cell epithelial-Mesenchymal transition in chronic pancreatitis-related diabetes. Diabetes 66, 2646–2658 (2017)

  78. S. Yamada, T. Fujii, Y. Shimoyama, M. Kanda, G. Nakayama, H. Sugimoto, M. Koike, S. Nomoto, M. Fujiwara, A. Nakao, Y. Kodera, SMAD4 expression predicts local spread and treatment failure in resected pancreatic Cancer. Pancreas 44, 660–664 (2015)

    Article  CAS  PubMed  Google Scholar 

  79. M. Zhao, L. Mishra, C.X. Deng, The role of TGF-beta/SMAD4 signaling in cancer. Int J Biol Sci 14, 111–123 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Dr. Glazer would like to acknowledge Dr. Ryan Fields and Dr. Williams Hawkins of Washington University in St. Louis for their kind donation of the KPC cell line and important scientific discussions. The authors would like to acknowledge the patients and staff at the Methodist University Hospital in Memphis, TN, USA, for contributing to the biorepository.

Funding

This work was supported by the UTHSC Center for Cancer Research, the UTHSC Cancer Biorepository (ESG) and a Society for Surgery of the Alimentary Tract Career Development Award (ESG). LM was also supported by NIH NCI CA253329.

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Authors and Affiliations

  1. Department of Surgery, College of Medicine, 910 Madison Ave., Suite 300, Memphis, TN, 38163, USA

    S. Mazher Hussain, Rita G. Kansal, Marcus A. Alvarez, T. J. Hollingsworth, Abul Elahi, Leah E. Hendrick, Paxton V. Dickson, Jeremiah L. Deneve, Danny Yakoub, David Shibata & Evan S. Glazer

  2. Department of Medicine, College of Medicine, Memphis, TN, USA

    Gustavo Miranda-Carboni, Ajeeth K. Pingili, Lorraine M. Albritton, D. Neil Hayes & Liza Makowski

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA

    Michio Kurosu & Liza Makowski

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  1. S. Mazher Hussain
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  2. Rita G. Kansal
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  17. Evan S. Glazer
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Contributions

Conception and design: SMH, DS, & ESG.

Development of methodology: SMH, DS, & ESG.

Acquisition of data: SMH, GMC, RGK, MAA, PVD, JLD, DS, ESG.

Analysis and interpretation of data: SMH, GMC, MK, DNH, DS, LM, & ESG.

Writing, reviewing and/or revising: all authors.

Study supervision: ESG.

Corresponding author

Correspondence to Evan S. Glazer.

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Study approval

All research has been approved by the Institutional Review Board (IRB) for human research and the Institutional Animal Use and Care Committee (IACUC) at UTHSC.

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There are no real or potential conflicts of interest.

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Hussain, S.M., Kansal, R.G., Alvarez, M.A. et al. Role of TGF-β in pancreatic ductal adenocarcinoma progression and PD-L1 expression. Cell Oncol. 44, 673–687 (2021). https://doi.org/10.1007/s13402-021-00594-0

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  • DOI: https://doi.org/10.1007/s13402-021-00594-0

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