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A CRISPR Knockout Screen Identifies Foxf1 as a Suppressor of Colorectal Cancer Metastasis That Acts Through Reduced mTOR Signalling

By Lennard Lee, Connor Woolley, Thomas Starkey, Luke Freeman-Mills, Andrew Bassett, Fanny Franchini, Lai Mun Wang, Annabelle Lewis, Roland Arnold, Ian Tomlinson

Posted 18 Apr 2019
bioRxiv DOI: 10.1101/613356

Introduction: A greater understanding of molecular mechanisms underlying metastasis is necessary for development of new strategies to prevent and treat cancer. Methods: We performed a genome-wide CRISPR/Cas9 knockout screen in MC38 colorectal cancer (CRC) cells transplanted orthotopically into mice to identify genes that promote metastasis. We undertook focussed molecular analyses to identify mechanisms underlying metastasis. Results: The screen identified several gene knockouts over-represented in lung metastases, including Dptor (mTOR signalling) and Foxf1 (gastrointestinal tumour predisposition). We validate that loss of Foxf1 promotes metastasis, increased Foxf1 expression restrained cellular migration in-vitro and human CRC metastases express lower Foxf1 than paired primary tumours. Analysis of gene expression changes downstream of Foxf1 identified increased mTOR signalling as a possible mechanism of metastasis caused by Foxf1 loss, consistent with Dptor identification. We confirmed this mechanism demonstrating that mTOR inhibitor sirolimus reduced lung metastasis burden in xenografts. Conclusion: Mesenchymal Foxf1 plays a major role in intestinal development. We have shown for the first time, through an unbiased genetic screen, that reduced epithelial Foxf1 results in raised mTOR signalling and metastasis.

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