Biology subjects

Astobiza, I.

Publications and source records attributed to Astobiza, I..

7 recordsLinked to original sources

bioRxiv2026

eRREMS expands regulatory CpG coverage in reduced representation methylome sequencing

Profiling the regulatory DNA methylation landscape remains technically challenging. Reduced-representation bisulfite sequencing (RRBS) misses distal enhancers and non-canonical regulatory elements, while whole-genome bisulfite sequencing (WGBS) distributes reads genome-wide, limiting consistent recovery of informative CpGs across sample collections. Here we present eRREMS (enhanced Reduced Representation Enzymatic Methylation Sequencing), addressing both limitations by combining MspI and HaeIII digestion with enzymatic cytosine conversion. eRREMS approximately doubles regulatory CpG recovery relative to standard RRBS, outperforming TaqI-based extended protocols, with gains concentrated in dynamically regulated enhancers, alternative promoters, and splicing-associated regions. HaeIII-specific CpGs capture additional complex trait heritability beyond standard RRBS. At modest, comparable sequencing depths, eRREMS achieves greater cohort-level completeness for regulatory and dynamically variable CpGs than WGBS and requires substantially fewer reads. CpG capture is stable across enzymatic conversion kits and library preparation conditions, supporting broad adoption. eRREMS provides a cost-efficient and reproducible strategy for scalable methylome profiling of regulatory CpGs across cohorts.

genomics↗

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

Loss of UFMylation supports prostate cancer metastasis and rewires cell metabolism towards hexosamine biosynthesis

The acquisition of metastatic features in tumor cells encompasses genetic and non-genetic adaptation, including reprogramming of cellular metabolism. Here we show that loss of UFMylation reroutes glucose metabolism, promotes invasive capacity and supports prostate cancer metastasis. Through transcriptome-based bioinformatics analysis, we identified a reduction in the ubiquitin-like modifier UFM1 and its ligase UFL1 in metastatic prostate cancer. We demonstrate that loss of UFMylation results in enhanced cancer cell dissemination and a switch from cellular proliferation to invasion. Using biotin-based proteomics, we identified phosphofructokinase (PFKAP) as an unprecedented UFMylation substrate. Consistent with UFMylation playing a role in the regulation of phosphofructokinase activity, loss of UFMylation reduced glucose metabolism in favour of hexosamine biosynthesis, which resulted in elevated glycosylation of proteins relevant for cell invasion. These results reveal a role for UFMylation in the regulation of phosphofructokinase and glucose metabolism to support prostate cancer metastasis.

cancer biology↗

bioRxiv2025

Transcription factor 19 is an androgen responsive gene that modulates vessel homeostasis and sustains metastatic prostate cancer

Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350.000 annual deaths worldwide. In turn, uncovering the molecular insights of metastatic disease is instrumental to improve the survival rate of prostate cancer patients. By means of gene expression metanalysis in multiple prostate cancer patient cohorts, we identified a set of genes that are differentially expressed in aggressive prostate cancer. Transcription factor 19 (TCF19) stood out as an unprecedented epithelial gene upregulated in metastatic disease, with prognostic potential and associated with the activity of androgen receptor. By combining computational and empiric approaches, our data revealed that TCF19 is required for full metastatic capacity and its depletion influences core cancer-related processes, such as vascular permeability, supporting the role of this gene in the dissemination of prostate tumor cells.

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↗

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↗