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

• Published in: Life science alliance 2020-06, Vol.3 (6), p.e201900573
• Main Authors: Parajuli, Parash, Nguyen, Thien Ly, Prunier, Céline, Razzaque, Mohammed S, Xu, Keli, Atfi, Azeddine
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Neutralizing - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Carcinoma, Pancreatic Ductal - complications; Carcinoma, Pancreatic Ductal - metabolism; Cells, Cultured; Diabetes Mellitus - etiology; Diabetes Mellitus - metabolism; Disease Models, Animal; Disease Progression; Gene Deletion; Insulin-Secreting Cells - metabolism; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pancreatic Neoplasms - complications; Pancreatic Neoplasms - metabolism; Prognosis; Receptor, Transforming Growth Factor-beta Type II - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; Smad4 Protein - genetics; Transforming Growth Factor beta1 - immunology; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.201900573

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 -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 or β ( ), 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.