TGFβ Signaling in the Pancreatic Tumor Microenvironment

SIMPLE SUMMARY: There is currently no effective treatment for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Transforming Growth Factor β (TGFβ) signaling has been implicated in several hallmark features of PDAC pathobiology, and TGFβ inhibitors are beginning to show promise in the treatment of PDAC. Here, we discuss the known roles of TGFβ signaling in the pancreatic tumor microenvironment, as well as clinical trials evaluating TGFβ pathway inhibitors in PDAC patients. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.