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Rho guanine nucleotide exchange factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma

Oncogene volume 39, pages 308–321 (2020)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human cancers, with 5-year patient survival rates of <5%. Activating mutations in KRAS are the predominant oncogenic drivers of PDAC but are accompanied by additional lower frequency genetic alterations. Our group previously identified the guanine nucleotide exchange factor ARHGEF10 in a genomic screen for genes with copy number alterations that may synergize with oncogenic KRAS to promote PDAC carcinogenesis. In the present study we show that ARHGEF10 possesses putative tumor suppressor function in PDAC. ARHGEF10 expression is reduced in over 70% of PDAC cell lines, and copy number loss is documented in more than 30% of PDAC patient-derived xenografts. Loss of ARHGEF10 expression enhanced subcutaneous tumor growth in mouse models, while its exogenous expression greatly impaired tumorigenesis. Loss of ARHGEF10 expression also increased in vitro proliferation, invasion, and motility of PDAC cell lines, and enhanced their metastatic spread in orthotopic mouse models. Treatment of ARHGEF10-depleted cells with the inhibitor dasatinib reduced levels of phospho Src kinase and attenuated motility and invasion in vitro. Together, our data indicate that ARHGEF10 may function as a tumor suppressor in PDAC.

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Acknowledgements

We thank Ming Li for his assistance with orthotopic implantation, Jing Xu for her assistance with immunohistochemistry, and Quan Li for his assistance with the analysis of gene expression data. This work was supported by the Canadian Cancer Society grant #700809, the Canadian Institutes of Health Research Foundation Scheme grant FDN-148395, and the Ontario Ministry of Health and Long Term Care. TW was supported by the Terry Fox Foundation Training Program in Molecular Pathology of Cancer at CIHR (STP 53912). Dr Tsao is the M. Qasim Choksi Chair in Lung Cancer Translational Research. The microarray data reported in this paper have been deposited into the Gene Expression Omnibus (GEO) database (accession number GSE131859).

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  1. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

    Joella Joseph, Nikolina Radulovich, Tao Wang, Vibha Raghavan, Chang-Qi Zhu & Ming-Sound Tsao

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

    Joella Joseph & Ming-Sound Tsao

  3. Department of Pathology, University Health Network, Toronto, Canada

    Tao Wang & Ming-Sound Tsao

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Correspondence to Ming-Sound Tsao.

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Joseph, J., Radulovich, N., Wang, T. et al. Rho guanine nucleotide exchange factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene 39, 308–321 (2020). https://doi.org/10.1038/s41388-019-0985-1

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