Acinar-to-ductal metaplasia induced by transforming growth factor beta facilitates KRAS(G12D)-driven pancreatic tumorigenesis

Chuvin, N. et al. (2017) Acinar-to-ductal metaplasia induced by transforming growth factor beta facilitates KRAS(G12D)-driven pancreatic tumorigenesis. Cellular and Molecular Gastroenterology and Hepatology, 4(2), pp. 263-282. (doi: 10.1016/j.jcmgh.2017.05.005) (PMID:28752115) (PMCID:PMC5524227)

Abstract

Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-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 TGFβ receptor (TβRICA) in the pancreatic acinar compartment. Results: We observed that TβRICA 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 Hnf1β, Sox9, and Hes1. Conclusions: We demonstrate that TGFβ 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.

• Item Type: Articles
• Keywords: ADM, acinar-to-ductal metaplasia, AFI, acinar fatty infiltration, Acinar-to-Ductal Metaplasia, Cancer, EMT, epithelial-to-mesenchymal transition, KRASG12D, PBS, phosphate-buffered saline, PDA, pancreatic ductal adenocarcinoma, PanIN, pancreatic intraepithelial neoplasia, Pancreas, RT-qPCR, reverse transcription quantitative polymerase chain reaction, TGFβ, TGFβ, transforming growth factor beta, TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vincent, Dr David and Morton, Professor Jen and Sansom, Professor Owen
• Authors: Chuvin, N., Vincent, D. F., Pommier, R. M., Alcaraz, L. B., Gout, J., Caligaris, C., Yacoub, K., Cardot, V., Roger, E., Kaniewski, B., Martel, S., Cintas, C., Goddard-Léon, S., Colombe, A., Valantin, J., Gadot, N., Servoz, E., Morton, J., Goddard, I., Couvelard, A., Rebours, V., Guillermet, J., Sansom, O. J., Treilleux, I., Valcourt, U., Sentis, S., Dubus, P., and Bartholin, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cellular and Molecular Gastroenterology and Hepatology
• Publisher: Elsevier
• ISSN: 2352-345X
• ISSN (Online): 2352-345X
• Published Online: 31 May 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Cellular and Molecular Gastroenterology and Hepatology 4(2): 263-282
• Publisher Policy: Reproduced under a Creative Commons license