| Added by | liaudet-coopman |
|---|---|
| Group name | EquipeELC |
| Item Type | Journal Article |
| Title | Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic Tumorigenesis |
| Creator | Chuvin et al. |
| Author | Nicolas Chuvin |
| Author | David F. Vincent |
| Author | Roxane M. Pommier |
| Author | Lindsay B. Alcaraz |
| Author | Johann Gout |
| Author | Cassandre Caligaris |
| Author | Karam Yacoub |
| Author | Victoire Cardot |
| Author | Elodie Roger |
| Author | Bastien Kaniewski |
| Author | Sylvie Martel |
| Author | Celia Cintas |
| Author | Sophie Goddard-Léon |
| Author | Amélie Colombe |
| Author | Julie Valantin |
| Author | Nicolas Gadot |
| Author | Emilie Servoz |
| Author | Jennifer Morton |
| Author | Isabelle Goddard |
| Author | Anne Couvelard |
| Author | Vinciane Rebours |
| Author | Julie Guillermet |
| Author | Owen J. Sansom |
| Author | Isabelle Treilleux |
| Author | Ulrich Valcourt |
| Author | Stéphanie Sentis |
| Author | Pierre Dubus |
| Author | Laurent Bartholin |
| Abstract | BACKGROUND & AIMS: Transforming growth factor beta (TGF?) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGF? activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGF?-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. METHODS: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGF? receptor (T?RICA) in the pancreatic acinar compartment. RESULTS: We observed that T?RI CA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1?, Sox9, and Hes1. CONCLUSIONS: We demonstrate that TGF? pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients. |
| Publication | Cellular and Molecular Gastroenterology and Hepatology |
| Volume | 4 |
| Issue | 2 |
| Pages | 263-282 |
| Date | Sep 2017 |
| Journal Abbr | Cell Mol Gastroenterol Hepatol |
| Language | eng |
| DOI | 10.1016/j.jcmgh.2017.05.005 |
| ISSN | 2352-345X |
| Library Catalog | PubMed |
| Extra | PMID: 28752115 PMCID: PMC5524227 |
| Tags | Acinar-to-Ductal Metaplasia, ADM, acinar-to-ductal metaplasia, AFI, acinar fatty infiltration, EMT, epithelial-to-mesenchymal transition, KRASG12D, original, PanIN, pancreatic intraepithelial neoplasia, PBS, phosphate-buffered saline, PDA, pancreatic ductal adenocarcinoma, RT-qPCR, reverse transcription quantitative polymerase chain reaction, TGF?, TGF?, transforming growth factor beta, TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling |
| Date Added | 2019/05/29 - 12:56:20 |
| Date Modified | 2019/05/29 - 12:56:47 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
Institut de Recherche en Cancérologie de
