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

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 beta-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-beta) signaling during PDAC progression caused erosion of beta-cell mass through apoptosis. Suppressing TGF-beta signaling, either pharmacologically through TGF-beta immunoneutralization or genetically through deletion of Smad4 or TGF-beta type II receptor (T beta RII), afforded substantial protection against PDAC-driven beta-cell depletion. From a translational perspective, both activation of TGF-beta signaling and depletion of beta-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.