TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1

Abstract

The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant KrasG12D. Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KPfl/flC mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.

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Acknowledgements

The authors acknowledge the assistance of Yi-Chen Chen, Pei-Rong Gu, and Hui-Ling Tung, as well as assistance from the following core facilities: the Clinical Medicine Research Center of National Cheng Kung University Hospital, the Animal Center of National Cheng Kung University, and the National Center for Genome Medicine (technical/bioinformatics). The authors would like to thank Drs Yi-Chuang Liao and Po-Min Chiang for pathological consultations and Dr Cindy Lee for manuscript editing. This work is supported by the Bi-institutional Collaborative Pancreatic Cancer Research grant from the College of Medicine of National Cheng Kung University to PJL and CSC; and grants MOST102-2320-B-006-050 and MOST104-2320-B-006-028- from the Ministry of Science and Technology, Taiwan, to PHH; MOHW104-TDU-B-211-124-003 from the Ministry of Health and Welfare, Taiwan, to YSS; and MOST 105-2321-B-001-064 from the Team of Excellent Research Program of the Ministry of Science and Technology, Taiwan, to CSC.

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Correspondence to Y-S Shan or C-S Chen.

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Huang, P., Lu, P., Ding, L. et al. TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1. Oncogene 36, 2202–2214 (2017). https://doi.org/10.1038/onc.2016.378

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