Biology subjects

Serrano, C.

Publications and source records attributed to Serrano, C..

6 recordsLinked to original sources

bioRxiv2025

Breaking the redundancy: TAZ outperforms YAP1 in GIST progression

BackgroundGastrointestinal stromal tumors (GIST) are mainly caused by gain-of-function mutations in KIT or PDGFRA genes and are the most common neoplasms of the digestive tract. Imatinib (IM), a tyrosine kinase inhibitor (TKI) targeting these oncogenic drivers, has considerably improved patient outcomes, although resistance remains a major challenge. The transcriptional co-activators YAP1 and TAZ, downstream effectors of the Hippo pathway, have emerged as potential oncogenic drivers in various cancers, including GIST. However, their specific roles in KIT-dependent tumor development remain unclear. MethodsWe used WRAP5-based nanoparticles loaded with specifically designed siRNA to selectively silence YAP1 and/or TAZ proteins in KIT-dependent IM-sensitive GIST cell lines. This nucleic acid delivery system enabled efficient and specific knockdown without cytotoxicity. We assessed the impact on cell proliferation, migration, and gene expression, focusing on YAP1/TAZ targets CYR61 and CTGF. ResultsTAZ silencing resulted in a substantial reduction in GIST-T1 cell proliferation and migration, whereas YAP1 knockdown was comparatively limited. This finding was consistent with an increased TAZ expression in GIST patients, which was associated with shorter progression-free survival and an increased tendency for metastasis development. A slight additive effect was observed upon a combined YAP1/TAZ silencing in the migration assay, suggesting a more complex regulation between these two proteins. CYR61 and CTGF expressions were predominantly regulated by TAZ, though a stronger downregulation was observed upon dual knockdown in a subset of GIST cell lines with differential YAP1 and TAZ basal expression. Finally, CYR61 seemed to be more implicated in cell proliferation inhibition, which is further supported by the correlation between high CYR61 expression and poor prognosis in the GIST patients. ConclusionOur results highlight the central regulatory function of TAZ-CYR61 axis in oncogenic processes in KIT-dependent GIST, with a modest contribution from YAP1. Targeting TAZ, alone or in combination with YAP1, may represent a promising therapeutic approach, particularly in the context of tumor heterogeneity.

cancer biology↗

bioRxiv2025

Pseudomonas species from Antarctica and other environments host diverse genes encoding structurally conserved polyhydroxyalkanoate synthases linked with different mobile genetic elements

Polyhydroxyalkanoates (PHAs) are industrial microbial biopolymers offering a sustainable and biodegradable alternative to petroleum-based plastics. The PHA polymerization process is primarily mediated by PHA synthases (PhaCs), which determine the molecular and physical properties of the synthesized polymers. Previous reports have described Antarctic Pseudomonas isolates with unique PhaCs and capabilities for PHA production. However, the genes encoding PhaCs in Pseudomonas from Antarctica and other environments have not been investigated systematically. Here, we studied the diversity and phylogenetic distribution of phaC genes in 186 Pseudomonas species, including 33 isolates from Antarctica. Most species encode two class II PhaCs, with some displaying additional class II and class I enzymes, especially in Antarctic isolates. Different PhaC subclasses were proposed based on this diversity. Some phaC genes are in putative genomic islands, phages, plasmids, or close to insertion sequences, supporting their acquisition by multiple routes of horizontal gene transfer. Remarkably, the Antarctic strain P. frigusceleri MPC6 harbors five PhaCs, including one from a potential novel class. These findings underscore the unique attributes and potential use of Antarctic Pseudomonas for biopolymer production. Future research is essential to elucidate the enzymatic properties of this underexplored PhaC diversity. Impact StatementA few Pseudomonas strains have been widely used to produce polyhydroxyalkanoates (PHAs), biopolymers constituting a sustainable alternative to petroleum-based plastics whose synthesis and properties primarily rely on PHA synthase enzymes (PhaCs). We showed that less-studied Pseudomonas species, especially from Antarctica, host a remarkable diversity of PhaCs, some likely acquired by horizontal transfer, including a potential novel class with yet-to-be-explored functional features and biotechnological potential.

microbiology↗

bioRxiv2024

MITF Targets in Gastrointestinal Stromal Tumors: Implication in Autophagy and Extracellular Vesicle Secretion

Previous studies have identified Microphthalmia-associated Transcription Factor (MITF) involvement in regulating Gastrointestinal Stromal Tumors (GIST) growth and cell cycle progression. This study uses Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing to explore MITF-modulated genes in GIST. Our findings reveal that MITF regulates genes involved in lysosome biogenesis, vesicle generation, autophagy, and mTOR signaling pathways. Comparative transcriptome analysis following MITF silencing in GIST cells shows differential enrichment in mTOR signaling, impacting tumor growth and autophagy. In the context of cancer, the interplay between autophagy and extracellular vesicle release can influence tumor progression and metastasis. We examined MITFs role in autophagy and extracellular vesicle (EV) production in GIST, finding that MITF overexpression increases autophagy, as shown by elevated LC3II levels while silencing MITF disrupts autophagosome and autolysosome formation. Despite no significant changes in EV size or number, MITF silencing notably reduces KIT expression in EV content. KIT secretion in EVs has been linked to GIST metastasis, suggesting that MITF is a crucial target for managing tumor growth and metastasis in GIST.

cancer biology↗

bioRxiv2023

Simple and Highly Specific Targeting of Resident Microglia with Adeno-Associated Virus

Microglia, as the immune cells of the central nervous system (CNS), play dynamic roles in both health and diseased conditions. The ability to genetically target microglia using viruses is crucial for understanding their functions and advancing microglia-based treatments. We here show that resident microglia can be simply and specifically targeted using adeno-associated virus (AAV) vectors containing a 466-bp DNA fragment from the human IBA1 (hIBA1) promoter. This targeting approach is applicable to both resting and reactive microglia. When combining the short hIBA1 promoter with the target sequence of miR124, up to 95% of transduced cells are identified as microglia. Such a simple and highly specific microglia-targeting strategy may be further optimized for research and therapeutics. Significance StatementBrain microglia play critical roles in human health and diseases. Genetic manipulation of these cells will offer numerous therapeutic opportunities. However, there is a lack of relevant strategies to target these cells with high specificity since they are traditionally considered to be refractory to virus transduction. Through in vivo screening of many promoters, this study identified a short promoter from the human IBA1 gene. When incorporated into lentivirus or adeno-associated virus vectors, this promoter proves effective in driving gene expression with high specificity for brain microglia. Such a simple strategy will facilitate specific approaches for microglia-based research.

neuroscience↗

bioRxiv2023

Tracking genome evolution in single cell clones reveals the rates and features of copy number alterations generated by ongoing chromosomal instability in cancer.

Cancer genomes exhibit extensive chromosomal alterations caused by ongoing Chromosomal Instability (CIN). The ensuing cell-cell heterogeneity facilitates evolution and cancer cell plasticity that can drive therapy resistance, yet cancer CIN driver mechanisms remain essentially uncharacterised. This lack of knowledge presents an untapped opportunity to target vulnerabilities associated with ongoing CIN for therapy. Existing methods to investigate the cellular mechanisms responsible for CIN rely on laborious functional assays, or inference from genomic alteration patterns from sequencing data. Current bulk sequencing derived copy number alteration pattern signatures lack the cell-cell resolution that would reveal recent genomic alterations caused by CIN. Large-scale single cell sequencing of cancer cell populations is now emerging. However, it is not known whether the effects of selection still obscure the spectrum of genomic alterations caused by recent CIN. To address this, we employed a single-cell whole-genome sequencing (scWGS) clonal outgrowth technique, that allows us to track the real-time evolution of cancer genomes at the single-cell level. Single cancer cells surprisingly re-establish heterogeneity that matches their parental population within [~]22 generations. By comparing the features of copy number alterations at different evolutionary timepoints we reveal that some alteration types are likely under negative selection and are thus only apparent in the most recent cell divisions, and not in the parental population. In one cell line we identify a particular chromosome subject to recurrent chromosomal deletions, and validated that this chromosome wasinvolved frequently in mis-segregation events during anaphase using fluorescence In-Situ hybridisation.

cancer biology↗

bioRxiv2023

Exposure to an enriched environment improves colonic epithelial barrier integrity and attenuates mouse experimental colitis by modulating a Myc-driven gene regulatory network

Withdrawal StatementThe authors have withdrawn their manuscript owing to erroneous labeling in two figures that have recently come to light. Experiments aiming to confirm the data presented are underway. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

immunology↗