Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos

Prostate cancer (PC) is the most common male visceral cancer, and second leading cause of cancer mortality in men in the Western world. Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase ( Pb-Cre ) Pten -deficient mouse model of PC, we identified Arid1a loss as a driver in the development of metastatic disease. The insertion of transposon in the Arid1a gene resulted in a 60% reduction of Arid1a expression, and reduced tumour free survival ( SB:Pten fl/fl Arid1a INT median 226 days vs SB:Pten fl/fl Arid1a WT 293 days, p=0.02),with elevated rates of metastasis ( SB:Pten fl/fl Arid1a INT 75% lung metastasis rate vs 17% SB:Pten fl/fl Arid1a WT , p<0.001 ). We further generated a Pb-Cre Pten - and Arid1a -deficient mouse model, in which loss of Arid1a demonstrated a profound acceleration in tumorigenesis in Pten fl/fl mice compared to Pten loss alone ( Pb-Cre Pten fl/fl Arid1a +/+ median survival of 267 days vs Pb-Cre Pten fl/fl Arid1a fl/fl 103 days, p<0.0001). Our data revealed homozygous Arid1a loss is required to dramatically accelerate prostate tumourigenesis, resulting in tumours with a less differentiated phenotype and a disorganised stroma. Furthermore, Arid1a loss mediated tumour formation in the mouse involved both the anterior and dorsolateral lobes, a unique feature from Pten -loss and other reported PC GEMM where tumour formation tends to be limited to the anterior lobes. Analysis of RNA and ChIP -Sequencing data suggests Arid1a loss enhanced the function of AP-1 subunit cFos. In clinical PC cohort, ARID1A and cFos levels stratified an aggressive subset of PC with a poor survival outcome with a median of only 30 months.