Biology subjects

Valcarcel-Jimenez, L.

Publications and source records attributed to Valcarcel-Jimenez, L..

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↗

bioRxiv2022

FOXA2 controls the antioxidant response in FH-deficient cells independent of NRF2

Hereditary Leiomyomatosis and renal cell cancer (HLRCC) is a cancer syndrome caused by inactivating germline mutations in fumarate hydratase (FH) and subsequent accumulation of fumarate. Fumarate accumulation leads to the activation of an anti-oxidant response via nuclear translocation of the transcription factor NRF2. The activation of the anti-oxidant response is key for cellular survival in FH-deficient cells, yet the extent to which chromatin remodelling shapes the anti-oxidant response is currently unknown. Here, we explored the global effects of FH loss on the chromatin landscape to identify transcription factor networks involved in the highly remodelled chromatin landscape of FH-deficient cells. We identify FOXA2 as a key transcription factor which directly regulates anti-oxidant response genes and subsequent metabolic rewiring. Moreover, we also find that FOXA2 regulates anti-oxidant genes independent of the canonical anti-oxidant regulator NRF2. The identification of FOXA2 as an anti-oxidant regulator provides new insights into the molecular mechanisms behind cell responses to fumarate accumulation, and potentially provides new avenues for therapeutic intervention for HLRCC.

cancer biology↗

bioRxiv2022

HIRA loss transforms FH-deficient cells

Fumarate Hydratase (FH) is a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle. Germline mutations of FH lead to HLRCC, a cancer syndrome characterised by a highly aggressive form of renal cancer(1). Although HLRCC tumours metastasise rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas (2). How Fh1-deficient cells overcome these tumour suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR/Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of HIRA enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss enables the activation of MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.

cancer biology↗