Gonzalo-Paulano, A.; Macchia, A.; Schaub-Clerigue, A.; Lectez, B.; Armendariz-Martinez, U.; Lejona, I.; Martin-Martin, N.; Astobiza, I.; Alonso, P.; Azkargorta, M.; Elortza, F.; Aransay, A. M.; Rondon-Lorefice, I.; Mendizabal, I.; Egia-Mendikute, L.; Palazon, A.; Hermanova, I.; Azueta, A.; Loizaga-Iriarte, A.; Ugalde-Olano, A.; Carracedo, A.; Bravo-Cordero, J. J.; Valcarcel-Jimenez, L.; Torrano, V.

Despite the high curation rate of localized prostate cancer, the fraction of patients that progress to metastasis still accounts for thousands of deaths worldwide, underscoring the need to identify early molecular events that prime tumours for aggressive disease. Here, we demonstrate that loss of the metabolic transcriptional coactivator PGC1alpha drives early extracellular matrix (ECM) remodelling in PCa, functionally linking epithelial transcriptional programs to tumour microenvironment interactions. Using genetically engineered mouse models, we show that combined deletion of Pten and Pgc1alpha induces early activation of ECMrelated transcriptional programs, increased collagen deposition, and a transition towards an aligned collagen fibre architecture, hallmarks of aggressive disease, prior to metastatic dissemination. Consistently, human prostate tumours with low PGC1alpha expression display increased collagen deposition, supporting the clinical relevance of these findings. Restoration of PGC1alpha expression in prostate cancer cells suppresses cell adhesion to multiple ECM substrates, disrupts collagen organization, and impairs tumour growth in a transcription dependent manner. Through integrative matrisome proteomics and transcriptomics, we identify the secreted glycoprotein CTHRC1 as a key downstream effector that enhances the prognostic value of PGC1alpha in PCa patients. Functional loss and gain of function studies establish CTHRC1 expression as both necessary and sufficient to restore ECM adhesion, cytoskeletal organization, collagen architecture, and tumorigenic capacity in PGC1alpha expressing cells. Importantly, recombinant CTHRC1 rescues adhesion defects, indicating that its extracellular pool mediates this phenotype, whereas deglycosylation abolishes its pro-adhesive function, revealing a mechanistic requirement for glycosylation. Collectively, our findings uncover an early, cell-intrinsic ECM remodelling program driven by PGC1alpha loss and identify the PGC1alphaCTHRC1 axis as a mechanistic and clinically relevant regulator of PCa aggressiveness.