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

Parash Parajuli,Mohammed S Razzaque,Azeddine Atfi,Thien Ly Nguyen,Keli Xu,Céline Prunier

doi:10.26508/lsa.201900573

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 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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a median survival of less than 6 mo and a cumulative 5-yr survival rate of 3–7% (Hidalgo, 2010)
To investigate whether PDAC could affect pancreas endocrine functions, we used the KC mouse model of PDAC, which faithfully mimics the pancreatic intraepithelial neoplasia (PanIN) to PDAC progression observed in the human disease (Hingorani et al, 2003; Tuveson et al, 2004)
In keeping with previous studies (Hingorani et al, 2003; Tuveson et al, 2004), analysis of pancreatic sections from 6- to 12-mo-old KC mice stained with hematoxylin and eosin (H&E) or immunostained with antibodies to the ductal marker Cytokeratin 19 (CK19) or Mucin 5Ac (Muc5Ac) showed the presence of various tumor lesions, including PanIN-1, PanIN-2, and PanIN-3 as well as full-blown PDAC (Fig S1A)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a median survival of less than 6 mo and a cumulative 5-yr survival rate of 3–7% (Hidalgo, 2010). Activated KRAS induces cancer cell proliferation by increasing glucose consumption approximately ten times more than in normal cells, a phenomenon known as the Warburg effect (Hsu & Sabatini, 2008; Ying et al, 2012). Given this dependency on glucose, one would surmise that hyperglycemia, which is typically associated with diabetes, could play an instrumental role in the pathogenesis and progression of PDAC by providing the glucose needed to fuel the growth of cancer cells. The mechanisms underlying the detrimental association between PDAC and diabetes remain poorly understood

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Conclusion