IRE1 activity regulates tumour and microenvironment cell lineage states while stratifying localised and metastatic prostate cancer

PCa is in need of better risk stratification at diagnosis and treatment outcomes in patients at high risk of metastasis. The unfolded protein response (UPR) is an AR-dependent process.

However, the impact of the UPR transducer IRE1 on AR-dependent biology and treatment resistance has not been defined. We use diverse pre-clinical models of stress response to describe IRE1 activity impact on multiple disease stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution by developing a PCa-specific, IRE1 activity gene set (IRE1_18) reflecting both tumoral and micro-environmental niches.