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.

Keywords: EMT; PDAC; SMAD4; TGFβ; pancreatic cancer.

Figure 1

TGFβ signaling is activated through BMP or TGFβ ligands. Ligands bind the TGFβ receptor II (TβR-II) which recruits and phosphorylates TGFβ receptor I (TβR-I). In the canonical TGFβ pathway, TβR-I phosphorylates regulated SMAD (R-SMAD), SMAD2 and 3, or SMAD1, 5, and 8. SMAD4 forms a heterotrimeric complex with R-SMAD. Once translocated to the nucleus, SMAD proteins interact with transcription factors (TF) and a co-activator/co-repressor to regulate gene transcription. Signaling is stopped through inhibitory SMADs (I-SMAD), SMAD6 and 7, with the help of SMAD ubiquitination regulatory factors (Smurfs) 1 and 2. Phosphatase PP2A dephosphorylates receptors to stop the signal. Non-canonical TGFβ signaling regroups MAPKs including Erk, p38, JNK, PI3k/Akt, and the small GTPase pathway.

Figure 2

Effects of TGFβ depending of pancreatic ductal adenocarcinoma stages. At early stages, TGFβ acts as a tumor suppressor, by promoting cell-cycle arrest through repression of c-Myc expression and cyclin-dependent kinase (CDK), and through enhancement of CDK inhibitor (CDKI) expression, thereby enhancing apoptosis and stimulating differentiation of precursor cells into a less proliferative stage. At late stages, TGFβ acts as a tumor promoter through immune evasion by stimulation of regulatory T cells and by inhibition of natural killers (NKs), macrophages, T cells, and dendritic cells (DCs). TFGβ acts also on the microenvironment by promoting desmoplasia and angiogenesis, and it triggers epithelial-to-mesenchymal transition (EMT) through induction of expression of transcription factors Snail and Zeb1/2.

Figure 3

Effects of SMAD4 loss and potential therapeutic strategies in SMAD4 signaling. In normal cells, SMAD4 acts as an intracellular mediator of TGFβ. In SMAD4-null cells, loss of SMAD4 leads to upregulation of the cell cycle and phosphoglycerate kinase 1 (PGK1), leading to tumor promotion. Therapies based on SMAD4 can be direct by targeting SMAD4 miRNA regulators to modulate SMAD4 or indirect by targeting a downstream component. SMAD4 loss leads to the enhanced efficacy of agents modulating the cell cycle, whereby SMAD4 as a biomarker could be useful to stratify therapies.