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// Jeffrey C. Francis 1 , Amy Capper 1 , Jian Ning 2 , Eleanor Knight 2 , Johann de Bono 3 and Amanda Swain 1, 2 1 Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK 2 Tumour Profiling Unit, The Institute of Cancer Research, London SW3 6JB, UK 3 Division of Clinical Studies, The Institute of Cancer Research, London SM2 5NG, UK Correspondence to: Amanda Swain, email: amanda.swain@icr.ac.uk Keywords: aggressive invasive prostate cancer; prostate cancer mouse models; cell lineage plasticity; epithelial to mesenchymal transition Received: May 18, 2017 Accepted: July 03, 2017 Published: January 10, 2018 ABSTRACT Aggressive lethal prostate cancer is characterised by tumour invasion, metastasis and androgen resistance. Understanding the mechanisms by which localised disease progresses to advanced lethal stages is key to the development of effective therapies. Here we have identified a novel role for the transcription factor, SOX9, as a driver of aggressive invasive prostate cancer. Using genetically modified mouse models, we show that increased Sox9 expression in the prostate epithelia of animals with Pten loss leads to a highly invasive phenotype and metastasis. In depth analysis of these mice and related in vitro models reveals that SOX9 acts a key regulator of various processes that together promote tumour progression. We show that this factor promotes cell lineage plasticity with cells acquiring properties of basal stem cells and an increase in proliferation. In addition, increased SOX9 leads to changes in cytoskeleton and adhesion, deposition of extracellular matrix and epithelia to mesenchyme transition, properties of highly invasive cells. Analysis of castrated mice showed that the invasive phenotype driven by SOX9 is independent of androgen levels. Our study has identified a novel driver of prostate cancer progression and highlighted the cellular and molecular processes that are regulated by Sox9 to achieve invasive disease.