SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma.

Julie Dardare,Andréa Witz,Jean-Louis Merlin,Alexandre Harlé,Pauline Gilson

doi:10.3390/ijms21103534

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas, with an extremely poor prognosis with a five-year survival rate of 5% and a median survival of less than 11 months [1]
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Inactivation of SMAD4 leads to a modification in transforming growth factor β (TGFβ) responses, promoting non-canonical TGFβ signaling which is linked to pro-tumorigenic responses

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas, with an extremely poor prognosis with a five-year survival rate of 5% and a median survival of less than 11 months [1]. For patients with unresectable or potentially resectable PDAC, most common therapies used in cancer treatment including chemotherapy or radiotherapy are limited due to a remarkable treatment resistance. Gemcitabine was the standard of care for more than two decades in patients with pancreatic cancer, after demonstrating significant improvement in overall survival (5.6 months as compared with 4.4 months for fluorouracil-based regimen; p = 0.0022) [5]. The FOLFIRINOX protocol including fluorouracil, leucovorin, irinotecan, and oxaliplatin is the first-line option for patients with metastatic pancreas cancer or in adjuvant settings with a better efficacy compared to gemcitabine [6,7]. Nab-paclitaxel represents an alternative in association with gemcitabine in metastatic PDAC patients, with a median overall survival of 8.5 months (hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.62, 0.83; p < 0.001) [8]

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