Biology subjects

Hermanova, I.

Publications and source records attributed to Hermanova, I..

4 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↗

bioRxiv2024

Secreted spermidine synthase reveals a paracrine role for PGC1a-induced growth suppression in prostate cancer

Prostate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1 expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1 governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1 loss of expression revealed that PGC1 alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1-dependent ERR regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media. The integration of in vitro and in vivo secretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1 and mediator of a paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1-ERR-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous tumor suppression role of PGC1, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.

cancer biology↗

bioRxiv2022

STAT3 restricts prostate cancer metastasis and antiandrogen resistance by controlling LKB1/CREB signaling pathway

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.

cancer biology↗

bioRxiv2018

Integrative analysis of transcriptomic and clinical data uncovers the tumor suppressive activity of MITF in prostate cancer.

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

cancer biology↗