Biology subjects

Mata, J.

Publications and source records attributed to Mata, J..

5 recordsLinked to original sources

bioRxiv2025

Discovery and therapeutic exploitation of Master Regulatory miRNAs in Glioblastoma

Glioblastoma is a fatal primary malignant brain tumor, with an average survival of only 15 months despite surgical resection, chemotherapy, and radiation therapy. Due to the concurrent deregulation of numerous genes in glioblastoma, molecular monotherapies have not improved clinical outcomes. Evidence suggests that effectively targeting multiple deregulated molecules is essential for better therapies; however, this is limited by the lack of suitable drugs and the increased toxicity of combination therapies. To address this, we hypothesized that miRNAs, small gene-regulatory RNAs that suppress multiple target genes via sequence complementarity, could be developed to inhibit multiple deregulated genes simultaneously, leading to more effective treatments. We identified master regulatory miRNAs--those that target several deregulated genes in glioblastoma--using PAR-CLIP screenings in glioblastoma cells and analyzed TCGA tumor data to find which targets were deregulated. An algorithm ranked these targets based on their significance in glioblastoma malignancy. We selected two tumor suppressor master regulatory miRNAs, miR-340 and miR-382, and one oncogenic miRNA, miR-17. Validation showed that these miRNAs target critical glioblastoma pathways and significantly inhibit cell growth, survival, invasion, and tumor growth in vivo. We developed an innovative therapeutic delivery approach using Brain Penetrating Nanoparticles in combination with MRI-guided focused ultrasound and microbubbles, resulting in reduced tumor volume and extended survival in glioblastoma-bearing mice. This strategy offers a promising pathway for translating miRNA-based therapies into clinical trials for glioblastoma and other cancers. One Sentence SummaryWe developed and used new computational, experimental, and therapeutic approaches to identify and therapeutically deliver master regulatory miRNAs to inhibit the growth of glioblastoma, the most common and deadly primary brain tumor.

cancer biology↗

bioRxiv2024

Tuning non-linear mechanics in collagen hydrogels modulates three dimensional cellular morphotypes

Collagen networks contribute to tissue architecture and modulate cellular responses in crowded three-dimensional environments. Therefore, it is the most widely used biological polymer in three-dimensional studies of cellular interactions with the extracellular matrix. In vivo, collagen exists embedded within additional matrix components. Studies have shown that the combination of matrices induces synergistic mechanical interactions, influencing the non-linear mechanical behaviour of collagen networks. However, how cells respond to changes in collagen non-linear elasticity remains largely unknown. By precisely controlling the mechanical behaviour of collagen networks with the biologically inert and semiflexible polymer polyisocyanopeptides, we demonstrate that changes in the non-linear elasticity of collagen induces morphological cell responses that influence how cells migrate, proliferate, and interact with collagen. We found that when collagen rigidifies in the presence of a second component, this induces morphological changes in cell-matrix interactions, resulting in a decrease in migration and the ability of cells to deform collagen matrices. Our results demonstrate that the onset of collagen stiffening is key to inducing intracellular tension which dictates morphological cell responses in three-dimensional collagen networks. We anticipate our findings will prove useful in understanding how cells respond to changes in collagen mechanics when combined in double network systems which better recapitulates tissues in vivo.

biophysics↗

bioRxiv2021

Fission stories: Using PomBase to understand Schizosaccharomyces pombe biology

PomBase (www.pombase.org), the model organism database (MOD) for the fission yeast Schizosaccharomyces pombe, supports research within and beyond the S. pombe community by integrating and presenting genetic, molecular, and cell biological knowledge into intuitive displays and comprehensive data collections. With new content, novel query capabilities, and biologist-friendly data summaries and visualisation, PomBase also drives innovation in the MOD community.

bioinformatics↗

bioRxiv2020

Ribosome profiling reveals ribosome stalling on tryptophan codons upon oxidative stress in fission yeast

Modulation of translation is an essential response to stress conditions. We have investigated the translational programmes launched by the fission yeast Schizosaccharomyces pombe subject to five environmental stresses: oxidative stress, heavy metal, heat shock, osmotic shock and DNA damage. We also explored the contribution of two major defence pathways to these programmes: The Integrated Stress Response, which directly regulates translation initiation, and the stress-response MAPK pathway. To obtain a genome-wide and high-resolution view of this phenomenon, we performed ribosome profiling of control cells and of cells subject to each of the five stresses mentioned above, both in wild type background and in cells in which the Integrated Stress Response or the MAPK pathway were inactivated. Translational changes were partially dependent on the integrity of both signalling pathways. Interestingly, we found that the transcription factor Fil1, a functional homologue of the Gcn4 and Atf4 proteins (from budding yeast and mammals, respectively), was highly upregulated in most stresses. Consistent with this result, Fil1 was required for the normal response to most stresses. A large group of mRNAs were translationally downregulated, including many required for ribosome biogenesis. Overall, our data suggest that severe stresses lead to the implementation of a universal translational response, which includes energy-saving measures (reduction of ribosome production) and induction of a Fil1-mediated transcriptional programme. Surprisingly, ribosomes stalled on tryptophan codons specifically upon oxidative stress, a phenomenon that is likely caused by a decrease in charged tRNA-Tryptophan. Tryptophan stalling led to a mild translation elongation reduction and contributed to the inhibition of initiation by the Integrated Stress Response. Taken together, our results show that different stresses elicit common and specific translational responses, revealing a special and so far unknown role in Tryptophan-tRNA availability.

molecular biology↗

bioRxiv2017

Long non-coding RNA repertoire and regulation by nuclear exosome, cytoplasmic exonuclease and RNAi in fission yeast

Transcriptomes feature pervasive, but poorly defined long non-coding RNAs (lncRNAs). We identify 5775 novel lncRNAs in Schizosaccharomyces pombe, nearly 4-times the previously annotated lncRNAs. Most lncRNAs become derepressed under genetic and physiological perturbations, especially during late meiosis. These lncRNAs are targeted by three RNA-processing pathways: the nuclear exosome, cytoplasmic exonuclease and RNAi, with substantial coordination and redundancy among pathways. We classify lncRNAs into cryptic unstable transcripts (CUTs), Xrn1-sensitive unstable transcripts (XUTs), and Dicer-sensitive unstable transcripts (DUTs). XUTs and DUTs are enriched for antisense lncRNAs, while CUTs are often bidirectional and actively translated. The cytoplasmic exonuclease and RNAi repress thousands of meiotically induced RNAs. Antisense lncRNA and sense mRNA expression often negatively correlate in the physiological, but not the genetic conditions. Intergenic and bidirectional lncRNAs emerge from nucleosome-depleted regions, upstream of positioned nucleosomes. This broad survey of the S. pombe lncRNA repertoire and characteristics provides a rich resource for functional analyses.

genomics↗