Transcriptional network analysis of PTEN protein-deficient prostate tumors reveals robust stromal reprogramming and signs of senescent paracrine communication

Among the extensive genomic alterations in prostate cancer, PTEN deletion stands out as one of the most consistently observed events. PTEN loss in prostate tumors is primarily associated with cancer cell proliferation and survival through the activation of the PI3K-AKT-mTOR signaling pathway. However, the use as a robust biomarker in clinical practice is hampered by its complex epigenetic, transcriptional, and post-translational regulation. In situ protein assessment by immunohistochemistry (IHC) captures PTEN protein status, but it does not report on associated tumor microenvironment remodeling. Here, we undertook an approach that combined PTEN immunoreactivity analysis with high-throughput transcriptional analysis to gain insights into the downstream functional effects of PTEN protein loss in primary tumors. Our extensive bioinformatic analyses highlighted stromal remodeling as a prominent cancer cell-extrinsic process associated with PTEN loss. By extending our transcriptomic computational strategy to Pten-loss driven murine prostate cancer, we validated the causal role of Pten in the stromal reaction observed in clinical specimens. Mechanistically, we provide experimental evidence for the activation of a paracrine program that encompasses enhanced TGF-β signaling and that is compatible with the secretome of PTEN-deficient senescent cancer cells. Finally, our findings enable the sub-stratification of tumors with PTEN loss based on their senescence-associated stroma remodeling program to distinguish indolent from aggressive cases. Our study provides relevant biological context to the cellular and molecular alterations unleashed upon PTEN protein loss in prostate cancer.