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Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to...

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Autores principales: Bangs, Fiona K., Miller, Paul, O'Neill, Eric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406310/
https://www.ncbi.nlm.nih.gov/pubmed/32571902
http://dx.doi.org/10.1242/dmm.044289
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author Bangs, Fiona K.
Miller, Paul
O'Neill, Eric
author_facet Bangs, Fiona K.
Miller, Paul
O'Neill, Eric
author_sort Bangs, Fiona K.
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas; however, in the presence of oncogenic KRAS, regeneration is blocked and ADM can give rise to PanIN lesions. Here, we used a 3D mouse acinar culture that recapitulates ADM in vitro to explore how KRAS prevents regeneration. Regeneration is regulated by Hedgehog (Hh) signalling, which is transduced via the primary cilium. In wild-type acini, cilia assemble upon ADM and Hh target gene expression is upregulated; however, ciliogenesis and Hh signalling are suppressed during ADM in cells expressing oncogenic KRAS. We show that ciliogenesis fails due to ectopic activation of the cilium disassembly pathway, which is mediated by AurkA, a direct transcriptional target of KRAS. Inhibition of AurkA is able to rescue primary cilia and restore Hh signalling. We suggest that this could be used as a mechanism to prevent the formation of early lesions and thereby prevent progression to PDAC.
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spelling pubmed-74063102020-08-06 Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse Bangs, Fiona K. Miller, Paul O'Neill, Eric Dis Model Mech Research Article Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas; however, in the presence of oncogenic KRAS, regeneration is blocked and ADM can give rise to PanIN lesions. Here, we used a 3D mouse acinar culture that recapitulates ADM in vitro to explore how KRAS prevents regeneration. Regeneration is regulated by Hedgehog (Hh) signalling, which is transduced via the primary cilium. In wild-type acini, cilia assemble upon ADM and Hh target gene expression is upregulated; however, ciliogenesis and Hh signalling are suppressed during ADM in cells expressing oncogenic KRAS. We show that ciliogenesis fails due to ectopic activation of the cilium disassembly pathway, which is mediated by AurkA, a direct transcriptional target of KRAS. Inhibition of AurkA is able to rescue primary cilia and restore Hh signalling. We suggest that this could be used as a mechanism to prevent the formation of early lesions and thereby prevent progression to PDAC. The Company of Biologists Ltd 2020-07-30 /pmc/articles/PMC7406310/ /pubmed/32571902 http://dx.doi.org/10.1242/dmm.044289 Text en © 2020. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Bangs, Fiona K.
Miller, Paul
O'Neill, Eric
Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse
title Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse
title_full Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse
title_fullStr Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse
title_full_unstemmed Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse
title_short Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse
title_sort ciliogenesis and hedgehog signalling are suppressed downstream of kras during acinar-ductal metaplasia in mouse
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406310/
https://www.ncbi.nlm.nih.gov/pubmed/32571902
http://dx.doi.org/10.1242/dmm.044289
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