Biology subjects

Rovira, Q.

Publications and source records attributed to Rovira, Q..

5 recordsLinked to original sources

bioRxiv2026

MET inhibition exploits conserved regulatory dependencies in malignant rhabdoid tumors

Malignant rhabdoid tumors (MRTs) are lethal, yet genomically simple childhood cancers characterised by universal SWI/SNF dysregulation. Despite this shared molecular framework, the regulatory programs sustaining MRTs and how they wire actionable dependencies, remain poorly defined. Here, we integrated single-cell multi-omic profiling and spatial transcriptomics across anatomically and molecularly diverse MRTs, generating a comprehensive multimodal MRT dataset at single-cell resolution. We leveraged this resource to identify candidate tumor-specific dependencies, which were subsequently functionally validated in vitro and in vivo in matched patient-derived models. We found that distinct malignant subpopulations are spatially patterned in complex environmentally shaped topologies, consistent with reciprocal interactions with stromal and immune compartments contributing to intratumoral transcriptional diversity. We identified recurrent transcriptional metaprograms conserved across patients and molecular subtypes, including a previously undescribed shared core rhabdoid program, as well as a metaprogram characterized by extracellular matrix interactions, and preferentially localized in tumor-stroma intermixed neighborhoods, supporting identification of niche conditioning cues. Mechanistically, we identified regulatory wiring driving these metaprograms, with the core shared rhabdoid programme coordinated by a circuit centred on TCF12, ZNF148 and CHD2. Guided by target nominations from our integrated analyses, we performed a curated drug screen using patient-derived MRT models and validated HGF/MET signaling as a selective vulnerability in extrarenal rhabdoid tumors. Pharmacologic MET inhibition was cytotoxic in sensitive models and induced a complete response in vivo using a clinically approved compound. Importantly, MET expression in primary tumors correlated with response, supporting biomarker-guided patient stratification for immediate clinical translation. Collectively, our findings define the molecular architecture of MRTs, reveal conserved regulatory programs beyond anatomical and molecular subtypes, and highlight a targetable signaling axis with immediate translational potential, establishing a framework for precision therapy in this lethal pediatric malignancy.

cancer biology↗

bioRxiv2024

Spatio-temporal T cell tracking for personalized TCR-T designs in childhood cancer

Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers. Here, we present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized TCR-T cell therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood. Specifically, we tracked T cell dynamics longitudinally from the tumor to cells in circulating over a time course of 12 months, revealing a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T cell dynamics in the blood post-ICI to predict tumor-reactivity. These findings strongly support spatio-temporal tracking of T cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.

genomics↗

bioRxiv2023

Specific photoreceptor cell fate pathways are differentially altered in NR2E3-associated diseases

Mutations in NR2E3 cause two retinal dystrophies with a distinct phenotype. NR2E3 encodes an orphan nuclear transcription factor that contributes to photoreceptor cell fate determination by repressing cone while activating rod genes. To dissect NR2E3 function, we performed scRNA-seq in the retinas of wild type and two different Nr2e3 mouse models that show phenotypes similar to patients carrying NR2E3 mutations. Our results reveal that rod and cone populations are not homogeneous and can be separated into different sub- classes. We identify a previously unreported cone pathway that generates hybrid cones that co-express both cone- and rod-related genes. In mutant retinas, this hybrid cone subpopulation is more abundant, as it includes a subpopulation of rods transitioning towards a cone cell fate. Hybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. Overall, our results shed light on the role of NR2E3 in modulating photoreceptor differentiation towards cone and rod fates and explain how mutations in NR2E3 lead to different visual disorders in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/543550v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@bc8118org.highwire.dtl.DTLVardef@1bf5f72org.highwire.dtl.DTLVardef@11351f5org.highwire.dtl.DTLVardef@169e7df_HPS_FORMAT_FIGEXP M_FIG C_FIG SYNOPSISMutations in the gene encoding the retinal transcription factor NR2E3 cause two different inherited retinal dystrophies: retinitis pigmentosa and enhanced S-cone syndrome. O_LIscRNA-seq in retinas of wild type and two Nr2e3 mouse models reveal that rod and cone populations are not homogeneous and can be classified into different sub-classes. C_LIO_LIA previously unreported cone pathway that generates hybrid cones co- expressing both cone- and rod-related genes is identified. C_LIO_LIHybrid photoreceptors with high misexpression of cone- and rod-related genes are prone to regulated necrosis. C_LIO_LIExpression of rod and cone signature genes change in response to different NR2E3 mutations thus providing a frame to understand the molecular basis of distinct NR2E3-associated diseases. C_LI

genetics↗

bioRxiv2021

A genomic portrait of zebrafish transposable elements and their spatiotemporal embryonic expression

There is considerable interest in understanding the effect of transposable elements (TEs) on embryonic development. Studies in humans and mice are limited by the difficulty of working with mammalian embryos, and by the relative scarcity of active TEs in these organisms. Zebrafish is an outstanding model for the study of vertebrate development and over half of its genome consists of diverse TEs. However, zebrafish TEs remain poorly characterized. Here we describe the demography and genomic distribution of zebrafish TEs and their expression throughout embryogenesis using bulk and single-cell RNA sequencing data. These results reveal a highly dynamic genomic ecosystem comprising nearly 2,000 distinct TE families, which vary in copy number by four orders of magnitude and span a wide range of ages. Longer retroelements tend to be retained in intergenic regions, whilst short interspersed nuclear elements (SINEs) and DNA transposons are more frequently found nearby or within genes. Locus-specific mapping of TE expression reveals extensive TE transcription during development. While two thirds of TE transcripts are likely driven by nearby gene promoters, we still observe stage and tissue-specific expression patterns in self-regulated TEs. Long terminal repeat (LTR) retroelements are most transcriptionally active immediately following zygotic genome activation, whereas DNA transposons are enriched amongst transcripts expressed in later stages of development. Single-cell analysis reveals several endogenous retroviruses expressed in specific somatic cell lineages. Overall, our study provides an important resource for using zebrafish as a model to study the impact of TEs on vertebrate development.

genomics↗

bioRxiv2020

A developmentally programmed splicing failure attenuates the DNA damage response during mammalian zygotic genome activation

The transition from maternal to embryonic transcriptional control is a crucial step in embryogenesis. However, how alternative splicing is regulated during this process and how it contributes to early development is unknown. Using transcriptomic data from pre-implantation stages of human, mouse and cow, we show that the stage of zygotic genome activation (ZGA) exhibits the highest levels of exon skipping diversity reported for any cell or tissue type. Interestingly, much of this exon skipping is temporary, leads to disruptive non-canonical isoforms, and occurs in genes enriched for DNA damage response in the three species. We identified two core spliceosomal components, Snrpb and Snrpd2, as regulators of these patterns. These genes have low maternal expression at the time of ZGA and increase sharply thereafter. Consistently, microinjection of Snrpb/d2 mRNA into mouse zygotes reduces the levels of temporary exon skipping at ZGA, and leads to an increase in etoposide-induced DNA damage response. Altogether, our results suggest that mammalian embryos undergo an evolutionarily conserved and developmentally programmed specific splicing failure at the time of genome activation that attenuates cellular responses to DNA damage at these early stages.

developmental biology↗