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

Parash Parajuli, Thien Ly Nguyen, Céline Prunier, View ORCID ProfileMohammed S Razzaque, View ORCID ProfileKeli Xu, View ORCID ProfileAzeddine Atfi  Correspondence email
Parash Parajuli
1Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
2Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
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Thien Ly Nguyen
1Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
2Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
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Céline Prunier
3Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Paris, France
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Mohammed S Razzaque
4Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA
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  • ORCID record for Mohammed S Razzaque
Keli Xu
2Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
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Azeddine Atfi
1Cellular and Molecular Pathogenesis Division, Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
2Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
3Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, Paris, France
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  • For correspondence: azeddine.atfi@inserm.fr
Published 5 May 2020. DOI: 10.26508/lsa.201900573
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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.

  • Received October 7, 2019.
  • Revision received April 21, 2020.
  • Accepted April 23, 2020.
  • © 2020 Parajuli et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Pancreatic cancer-associated diabetes
Parash Parajuli, Thien Ly Nguyen, Céline Prunier, Mohammed S Razzaque, Keli Xu, Azeddine Atfi
Life Science Alliance May 2020, 3 (6) e201900573; DOI: 10.26508/lsa.201900573

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Pancreatic cancer-associated diabetes
Parash Parajuli, Thien Ly Nguyen, Céline Prunier, Mohammed S Razzaque, Keli Xu, Azeddine Atfi
Life Science Alliance May 2020, 3 (6) e201900573; DOI: 10.26508/lsa.201900573
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Volume 3, No. 6
June 2020
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