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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 unfo...

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Autores principales: Parajuli, Parash, Nguyen, Thien Ly, Prunier, Céline, Razzaque, Mohammed S, Xu, Keli, Atfi, Azeddine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211975/
https://www.ncbi.nlm.nih.gov/pubmed/32371554
http://dx.doi.org/10.26508/lsa.201900573
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author Parajuli, Parash
Nguyen, Thien Ly
Prunier, Céline
Razzaque, Mohammed S
Xu, Keli
Atfi, Azeddine
author_facet Parajuli, Parash
Nguyen, Thien Ly
Prunier, Céline
Razzaque, Mohammed S
Xu, Keli
Atfi, Azeddine
author_sort Parajuli, Parash
collection PubMed
description 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 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.
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spelling pubmed-72119752020-05-15 Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells Parajuli, Parash Nguyen, Thien Ly Prunier, Céline Razzaque, Mohammed S Xu, Keli Atfi, Azeddine Life Sci Alliance Research Articles 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 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. Life Science Alliance LLC 2020-05-05 /pmc/articles/PMC7211975/ /pubmed/32371554 http://dx.doi.org/10.26508/lsa.201900573 Text en © 2020 Parajuli et al. https://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/).
spellingShingle Research Articles
Parajuli, Parash
Nguyen, Thien Ly
Prunier, Céline
Razzaque, Mohammed S
Xu, Keli
Atfi, Azeddine
Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
title Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
title_full Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
title_fullStr Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
title_full_unstemmed Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
title_short Pancreatic cancer triggers diabetes through TGF-β–mediated selective depletion of islet β-cells
title_sort pancreatic cancer triggers diabetes through tgf-β–mediated selective depletion of islet β-cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211975/
https://www.ncbi.nlm.nih.gov/pubmed/32371554
http://dx.doi.org/10.26508/lsa.201900573
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