Biology subjects

Loizaga-Iriarte, A.

Publications and source records attributed to Loizaga-Iriarte, A..

3 recordsLinked to original sources

bioRxiv2026

Loss of PGC1α drives extracellular matrix remodelling in prostate cancer through CTHRC1

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 PGC1 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 Pgc1 induces early activation of ECM-related 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 PGC1 expression display increased collagen deposition, supporting the clinical relevance of these findings. Restoration of PGC1 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 PGC1 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 PGC1-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 PGC1 loss and identify the PGC1-CTHRC1 axis as a mechanistic and clinically relevant regulator of PCa aggressiveness.

cancer biology↗

bioRxiv2025

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, the genomic deletion of PTEN stands out as one of the most consistently observed and confirmed alteration. PTEN loss in prostate tumors is primarily associated with cancer cell proliferation and survival through the activation of the PI3K-AKT-mTOR signalling pathway. However, its use as a robust biomarker in the clinical practice is hampered by the complex epigenetic, transcriptional and post-translational regulation. Here, we undertook an approach that combined in situ assessment of PTEN protein with transcriptional surrogates of its activity to gain insights into the downstream functional effects of PTEN loss in primary tumors. Our extensive bioinformatic analyses, including the integration with single-cell RNA-Seq approaches in a new clinical cohort, highlighted stroma remodeling as the major cancer cell-extrinsic process associated with PTEN loss. By applying similar computational strategy on the transcriptomic data generated from primary prostate tumors of genetically engineered Pten knock-out mouse models, we validated the causal role of Pten in the stromal reaction observed in clinical specimens. Mechanistically, we provide evidence for the activation of a paracrine program that encompasses enhanced TGF-{beta} signalling and that is compatible with the secretome of PTEN-deficient senescent cancer cells. Our study provides relevant biological context to the cellular and molecular alterations unleashed upon PTEN protein loss.

cancer biology↗

bioRxiv2024

The transcriptional landscape of metastatic hormone-naive prostate cancer

Metastatic hormone-naive prostate cancer (mHNPC) is an infrequent form of this tumour type that is characterized by metastasis at the time of diagnosis and accounts for 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration resistant prostate cancer (mCRPC), the molecular characteristics of mHNPC remain largely unexplored. Here we provide the first extensive transcriptomics characterization of mHNPC. We generated discovery and validation bulk and single-cell RNA-Seq datasets and performed integrative computational analysis in combination with experimental studies. Our results provide unprecedented evidence of the distinctive transcriptional profile of mHNPC and identify stroma remodelling as a predominant feature of these tumours. Importantly, we discover a central role for the transcription factor SOX11 in triggering a heterotypic communication that is associated to the acquisition of metastatic properties. Our study will constitute an invaluable resource for a profound understanding of mHNPC that can influence patient management.

cancer biology↗