Dataset Information

Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-? exposure.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease and a major health problem in the United States. While the cytokine TGF-? has been implicated in PDAC development, it can exert both pro-tumorigenic and anti-tumorigenic effects that are highly context dependent and incompletely understood. Using three-dimensional (3D) cultures of KrasG12D-expressing mouse pancreatic epithelial cells we demonstrated that while exposure to exogenous TGF-? induced growth arrest of the KrasG12D cells, its subsequent removal allowed the cells to enter a hyper-proliferative, partially mesenchymal (PM), and progenitor-like state. This state was highly stable and was maintained by autocrine TGF-? signaling. While untreated KrasG12D cells formed cystic lesions in vivo, PM cells formed ductal structures resembling human PanINs, suggesting that they had attained increased oncogenic potential. Supporting this hypothesis, we determined that the PM cells share salient molecular and phenotypic features with the quasi-mesenchymal/squamous subtype of human PDAC, which has the worst prognosis of any of the recently identified subtypes. Transient pulses of TGF-? have been observed during pancreatitis, a major risk factor for PDAC. Our data suggest that transient TGF-? exposure is sufficient to induce the acquisition of stable PDAC-associated phenotypes in pre-neoplastic KrasG12D cells, providing novel molecular insight into the complex role of TGF-? in tumorigenesis.

SUBMITTER: Handler J

PROVIDER: S-EPMC6076343 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-β exposure.

Handler Jesse J Cullis Jane J Avanzi Antonina A Vucic Emily A EA Bar-Sagi Dafna D

Oncogene 20180501 31

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease and a major health problem in the United States. While the cytokine TGF-β has been implicated in PDAC development, it can exert both pro-tumorigenic and anti-tumorigenic effects that are highly context dependent and incompletely understood. Using three-dimensional (3D) cultures of Kras<sup>G12D</sup>-expressing mouse pancreatic epithelial cells we demonstrated that while exposure to exogenous TGF-β induced growth arrest of the Kras<sup> ...[more]

PMID: 29713060

Similar Datasets

Project description:Transforming growth factor-beta (TGF-beta) superfamily signaling has been implicated in many developmental processes, including pancreatic development. Previous studies are conflicting with regard to an exact role for TGF-beta signaling in various aspects of pancreatic organogenesis. Here we have investigated the role of TGF-beta isoform signaling in embryonic pancreas differentiation and lineage selection. The TGF-beta isoform receptors (RI, RII and ALK1) were localized mainly to both the pancreatic epithelium and mesenchyme at early stages of development, but then with increasing age localized to the pancreatic islets and ducts. To determine the specific role of TGF-beta isoforms, we functionally inactivated TGF-beta signaling at different points in the signaling cascade. Disruption of TGF-beta signaling at the receptor level using mice overexpressing the dominant-negative TGF-beta type II receptor showed an increase in endocrine precursors and proliferating endocrine cells, with an abnormal accumulation of endocrine cells around the developing ducts of mid-late stage embryonic pancreas. This pattern suggested that TGF-beta isoform signaling may suppress the origination of secondary transition endocrine cells from the ducts. Secondly, TGF-beta isoform ligand inhibition with neutralizing antibody in pancreatic organ culture also led to an increase in the number of endocrine-positive cells. Thirdly, hybrid mix-and-match in vitro recombinations of transgenic pancreatic mesenchyme and wild-type epithelium also led to increased endocrine cell differentiation, but with different patterns depending on the directionality of the epithelial-mesenchymal signaling. Together these results suggest that TGF-beta signaling is important for restraining the growth and differentiation of pancreatic epithelial cells, particularly away from the endocrine lineage. Inhibition of TGF-beta signaling in the embryonic period may thus allow pancreatic epithelial cells to progress towards the endocrine lineage unchecked, particularly as part of the secondary transition of pancreatic endocrine cell development. TGF-beta RII in the ducts and islets may normally serve to downregulate the production of beta cells from embryonic ducts.

Dataset Information

Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-? exposure.

Publications

Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-β exposure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets