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However, the use of PTEN as a robust biomarker in clinical practice is hampered by its complex epigenetic, transcriptional and post\u2010translational regulation.\n                    <jats:italic>In situ<\/jats:italic>\n                    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\u2010throughput 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\u2010extrinsic process associated with PTEN loss. By extending our transcriptomic computational strategy to\n                    <jats:italic>Pten<\/jats:italic>\n                    loss\u2010driven murine prostate cancer, we validated the causal role of\n                    <jats:italic>Pten<\/jats:italic>\n                    in the stromal reaction observed in clinical specimens. Mechanistically, we provide experimental evidence for the activation of a paracrine program that encompasses enhanced transforming growth factor beta (TGF\u2010\u03b2) signaling and that is compatible with the secretome of\n                    <jats:italic>PTEN<\/jats:italic>\n                    \u2010deficient senescent cancer cells. Finally, our findings enable the sub\u2010stratification of tumors with PTEN loss based on their senescence\u2010associated 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.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70164","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T14:16:06Z","timestamp":1763388966000},"page":"1429-1452","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptional network analysis of\n                    <scp>PTEN<\/scp>\n                    \u2010protein\u2010deficient prostate tumors reveals robust stromal reprogramming and signs of senescent paracrine communication"],"prefix":"10.1002","volume":"20","author":[{"given":"Ivana","family":"Rondon\u2010Lorefice","sequence":"first","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA)  Derio 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