RT Journal Article
SR Electronic
T1 Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900573
DO 10.26508/lsa.201900573
VO 3
IS 6
A1 Parajuli, Parash
A1 Nguyen, Thien Ly
A1 Prunier, Céline
A1 Razzaque, Mohammed S
A1 Xu, Keli
A1 Atfi, Azeddine
YR 2020
UL http://www.life-science-alliance.org/content/3/6/e201900573.abstract
AB 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 KrasG12D-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.