SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.

Magnolol Suppresses Pancreatic Cancer Development In Vivo and In Vitro via Negatively Regulating TGF-β/Smad Signaling

“…A series of pathways including Wnt, β-catenin, Notch, and tyrosine kinases is related to the induction of EMT. Among them, TGF-β1 is known as not only an inflammatory cytokine but also a pivotal inducer and sustainer of EMT ( 20 ). EMT is closely involved in not only invasion and metastasis but also proliferation and chemotherapy resistance.…”

“…EMT is closely involved in not only invasion and metastasis but also proliferation and chemotherapy resistance. TGF-β-induced EMT plays an important role in PDAC progression, especially in metastases ( 20 ). Once bonded to its receptor on the cytomembrane, TGF-β induces phosphorylation of its downstream factors, including but not limited to SMAD proteins.…”

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

“…Subsequently, R-SMADs dissociate from the ligand-receptor complex after serine is phosphorylated by the receptor, and then associate with SMAD4 in the cytoplasm [ 50 ]. The complex consisting of R-SMADs and SMAD4 then enters the nucleus, and initiates the transcription of EMT-associated genes [ 51 ]. USP2 facilitates the binding of R-SMADs to TGF-β receptors by removing the K33-linked poly-ubiquitin chains on TGF-β receptors [ 52 ].…”

Pancreatic Fibroblast Heterogeneity: From Development to Cancer

“…Tumor cells that express wildtype Smad4 undergo EMT following TGF-β stimulation, but ultimately apoptose [ 154 ]. In contrast, mutations in Smad4 synergize with other oncogenic mutations (e.g., Kras G12D ) to drive PDA progression and tumor growth [ 143 , 154 , 155 , 156 ]. These data highlight the complex cross talk between the immune cells, tumor cells, and CAFs, and the importance of detailed characterization of these different signaling pathways within the TME.…”