TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment

Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment. Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment. Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers, represents a highly intractable type of human malignancy.1Kleeff J. Korc M. Apte M. La Vecchia C. Johnson C.D. Biankin A.V. Neale R.E. Tempero M. Tuveson D.A. Hruban R.H. Neoptolemos J.P. Pancreatic cancer.Nat. Rev. Dis. 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Gourgou-Bourgade S. de la Fouchardière C. et al.Groupe Tumeurs Digestives of UnicancerPRODIGE IntergroupFOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N. Engl. J. Med. 2011; 364: 1817-1825Crossref PubMed Scopus (3909) Google Scholar A less toxic, but also a less effective, alternative to FOLFIRINOX is a combination regimen of gemcitabine and nanoparticle albumin-bound (nab) paclitaxel which showed an improvement of overall survival, progression-free survival, and response rates as compared with gemcitabine alone; however, adverse effects such as myelosuppression and peripheral neuropathy were reported.10Von Hoff D.D. Ervin T. Arena F.P. Chiorean E.G. Infante J. Moore M. Seay T. Tjulandin S.A. Ma W.W. Saleh M.N. et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N. Engl. J. Med. 2013; 369: 1691-1703Crossref PubMed Scopus (3013) Google Scholar To conclude, despite multiple chemotherapy-based treatments for pancreatic cancer, only a marginal improvement of overall survival is achieved, which is often associated with a high risk of developing serious adverse effects. With PDAC-related death rates still on the rise, there is an urgent need for developing treatment paradigms that are capable of optimizing the response to chemotherapy and achieving significant overall survival benefits for pancreatic cancer patients. The cancer stem cell (CSC) hypothesis proposes that a subpopulation of cells possessing distinctive stemness features and functions, known as CSCs, are located at the apex of a hierarchical organization of cells within a tumor and are likely to be responsible for driving tumorigenesis and metastasis.11Bonnet D. Dick J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat. 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Chem. 2014; 289: 14520-14533Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Similarly, METhighCD44+ PCSCs displayed a self-renewal capacity as well as a high tumorigenic potential in immunocompromised mice, which was reduced upon treatment with MET inhibitors alone or in combination with gemcitabine.16Li C. Wu J.J. Hynes M. Dosch J. Sarkar B. Welling T.H. Pasca di Magliano M. Simeone D.M. c-Met is a marker of pancreatic cancer stem cells and therapeutic target.Gastroenterology. 2011; 141: 2218-2227.e5Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar The origin of PCSCs still remains unknown; however, there are two potential origins: either from normal somatic stem cells that have undergone transformative genetic alterations or mutated differentiated cells that have reprogrammed to acquire stem cell-like properties.17Hermann P.C. Mueller M.T. Heeschen C. Pancreatic cancer stem cells--insights and perspectives.Expert Opin. Biol. Ther. 2009; 9: 1271-1278Crossref PubMed Scopus (0) Google Scholar Thus, according to the CSC model, which is supported by in vitro cell-based assays and in vivo tumorigenicity studies, chemotherapy alone is unlikely to lead to complete tumor elimination, as the residual population of intrinsically chemoresistant CSCs are able to self-renew and differentiate indefinitely, leading to tumor regeneration (Figure 1). This review article discusses targeting PCSCs as one of the major roots of tumor relapse that regulate the development of resistance to chemotherapy through multiple mechanisms. We are mainly focusing here on the SMAD2/3-dependent transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer (Activin A)/Nodal signaling pathways, which are crucial for sustaining the stem cell-like characteristics of PCSCs, mediating bidirectional crosstalk between pancreatic cancer cells and components of the surrounding tumor microenvironment (TME), and regulating the properties of the PDAC-associated stroma. 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