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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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.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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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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