Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles (Data Paper) Life Science Alliance Year : 2020

Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfolding. Using a mouse model of Kras G12D -driven PDAC, which faithfully recapitulates the progression of the human disease, we observed a massive and selective depletion of β-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-β) signaling during PDAC progression caused erosion of β-cell mass through apoptosis. Suppressing TGF-β signaling, either pharmacologically through TGF-β immunoneutralization or genetically through deletion of Smad4 or TGF- β type II receptor ( TβRII ), afforded substantial protection against PDAC-driven β-cell depletion. From a translational perspective, both activation of TGF-β signaling and depletion of β-cells frequently occur in human PDAC, providing a mechanistic explanation for the pathogenesis of diabetes in PDAC patients, and further implicating new-onset diabetes as a potential early prognostic marker for PDAC.
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Dates and versions

inserm-04021579 , version 1 (09-03-2023)

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Parash Parajuli, Thien Ly Nguyen, Céline Prunier, Mohammed Razzaque, Keli Xu, et al.. Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells. Life Science Alliance, 2020, 3 (6), pp.e201900573. ⟨10.26508/lsa.201900573⟩. ⟨inserm-04021579⟩
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