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

Oncogene volume 37, pages 4334–4342 (2018)Cite this article

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Abstract

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 KrasG12D-expressing mouse pancreatic epithelial cells we demonstrated that while exposure to exogenous TGF-β 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-β 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-β have been observed during pancreatitis, a major risk factor for PDAC. Our data suggest that transient TGF-β 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-β in tumorigenesis.

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Acknowledgements

The authors thank L.J. Taylor for discussions and help with article preparation and the members of the Bar-Sagi laboratory for comments. The authors also thank the New York University School of Medicine Genome Technology Center (GTC), especially Adriana Heguy and Igor Dolgalev, for help designing, performing, and analyzing RNA sequencing experiments. The GTC is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work was further supported by NIH/NCI grant CA210263 (D. Bar-Sagi). J. Handler was supported by NIH grant T32GM007308. J. Cullis was supported by NIH grants 5-T32 CA 009161-39 and 5-T32AI100853-04. E.A. Vucic is supported by a Canadian Institutes of Health Research postdoctoral fellowship (146792).

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  1. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA

    Jesse Handler, Jane Cullis, Antonina Avanzi, Emily A. Vucic & Dafna Bar-Sagi

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Correspondence to Dafna Bar-Sagi.

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Handler, J., Cullis, J., Avanzi, A. et al. Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-β exposure. Oncogene 37, 4334–4342 (2018). https://doi.org/10.1038/s41388-018-0264-6

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