Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS G12D-driven Pancreatic Tumorigenesis

Cell Mol Gastroenterol Hepatol. 2017 May 31;4(2):263-282. doi: 10.1016/j.jcmgh.2017.05.005. eCollection 2017 Sep.

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.

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.