Biology subjects

Mateo-Lozano, S.

Publications and source records attributed to Mateo-Lozano, S..

4 recordsLinked to original sources

bioRxiv2026

RERE and the Mediator complex cooperate with EWSR1::FLI1 in the reprogramming of Translation and Alternative Splicing, the latter being a therapeutically targetable vulnerability in Ewing sarcoma

Ewing Sarcoma (ES) is an aggressive neoplasm arising in bones and soft tissues driven by the oncogenic fusion EWSR1::FLI1. Through epigenetic deregulation, EWSR1::FLI1 generates de novo super-enhancers that control the expression of key genes for tumor cell maintenance. By an integrative in silico analysis, we identified the subunit of the Mediator complex MED13L and RERE, a member of the atrophin family of arginine-glutamic acid dipeptide repeat-containing proteins, as genes regulated by EWSR1::FLI1-bound super-enhancers. We confirmed that EWSR1::FLI1 regulates MED13L and RERE expression in ES cell lines and showed that these proteins are highly expressed in Ewing primary tumors. Besides the well-established role of the Mediator complex in transcriptional regulation given its association with the RNA polymerase II, in ES cells the DNA binding sites of MED13L overlap with those of RERE and EWSR1::FLI1 in genes that control protein translation and alternative splicing (AS). Accordingly, the expression of various spliceosome components is co-regulated by MED13L, RERE and the oncogene, leading to AS in ES cells. We identified RBM39, a splicing factor downregulated after MED13L and RERE depletion, as a direct transcriptional target of EWSR1::FLI1. Consistently, in vitro viability experiments using indisulam, which induces selective DCAF15-dependent proteosome degradation of RBM39, demonstrate ES cells highly and specifically sensitive to RBM39 inhibition. In vivo experiments with mice xenografted with ES cells show complete tumor regression with indisulam, highlighting the potential of this approach as a novel and promising therapeutic strategy for Ewing sarcoma. STATEMENT OF SIGNIFICANCEEwing sarcoma (ES) is characterized by FET::ETS oncoproteins that act as pioneer transcription factors. Here, we identified two genes controlled by EWSR1::FLI1-bound super-enhancers, MED13L and RERE, and characterized the mechanism by which these proteins cooperate with the oncogene to regulate RNA metabolism and ribosomal processes in ES cells. These findings have led to the identification of the splicing factor RBM39 as a vulnerability in ES, as supported by the extraordinary sensitivity of these tumors to monotherapy with RBM39 degrader indisulam.

cancer biology↗

bioRxiv2026

USP7 sustains PAX3::FOXO1 enhancer reprogramming and represents a therapeutic vulnerability in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and is often associated with dismal outcomes, underscoring the urgent need for new therapeutic strategies. RMS arises from embryonic skeletal muscle precursor cells that fail to complete the myogenic differentiation program. Fusion-positive rhabdomyosarcoma (FP-RMS), defined by the presence of recurrent gene fusions such as PAX3::FOXO1 or PAX7::FOXO1, is associated with the poorest overall survival. The encoded fusion oncoprotein cause epigenetic reprogramming that defines the biology and behavior of FP-RMS. Polycomb repressive complex 1 (PRC1)-mediated chromatin regulation contributes to the control of developmental gene programs. Here, we investigate the dependency of RMS on epigenetic remodeling mediated by the PRC1.1 subunits ubiquitin specific protease 7 (USP7) and really interesting new gene 1B (RING1B). We found that USP7 is overexpressed in RMS samples, and that high expression correlates with poor patient prognosis. USP7 and RING1B bind to H3K27ac-enriched regions and colocalize with PAX3::FOXO1 at active enhancers controlling key tumorigenic genes in FP-RMS. Moreover, both shRNA-mediated depletion and pharmacological inhibition of USP7 downregulate PAX3::FOXO1 enhancer-driven genes, induce skeletal muscle differentiation and significantly inhibit FP-RMS tumor growth in vivo. Altogether, our findings identify USP7 as a critical regulator of PAX3::FOXO1-bound enhancers and highlight a novel therapeutic opportunity in RMS based on epigenetic dependencies.

cancer biology↗

bioRxiv2025

Integrative multi-omics reveals PARP14 as a key IFNγ-regulated mediator of metastatic progression in Ewing sarcoma.

Metastatic Ewing sarcoma (EwS) remains a major clinical challenge, highlighting the need to identify molecular drivers of disease dissemination. Through integrated transcriptomic, functional, and mechanistic analyses, we identify PARP14 as a key regulator of EwS metastatic progression. PARP14 is consistently upregulated in metastatic lesions across spontaneous and xenograft mouse models as well as in patient samples. Genetic and pharmacologic depletion of PARP14 (via siRNA knockdown, CRISPR-Cas9 knockout, or PROTAC-mediated degradation) significantly impaired EwS cell migration and invasion in vitro, without affecting proliferation or clonogenic capacity. In vivo, PARP14 loss delayed tumor growth and reduced metastatic burden, supporting a functional role in disease progression. Conversely, IFN{gamma}-induced PARP14 upregulation and stable overexpression enhanced EwS cell migration and increased lung metastasis formation. Transcriptomic profiling of PARP14-deficient cells revealed downregulation of invasive signatures and enrichment of inflammatory and p53-related pathways, together with gene sets associated with chromatin remodeling. Subcellular fractionation and interactome analyses showed that PARP14 localizes to cytoplasmic, nuclear, and chromatin-associated compartments, and interacts with chromatin, cytoskeletal and ECM regulators. ChlP analyses further demonstrated PARP14 binding to promoters enriched for NRF1 motifs, suggesting a role as a transcriptional co-regulator influencing gene networks relevant to EwS progression. Together, our results establish PARP14 as a contributor to EwS dissemination and uncover a previously unappreciated chromatin-associated role for this protein, supporting its potential as both a biomarker and therapeutic target in metastatic EwS. STATEMENT OF SIGNIFICANCEWe identify PARP14 as a novel driver of Ewing sarcoma metastasis through integrated multi-omics profiling. Genetic and pharmacological interrogation establishes PARP14 as a promising therapeutic target for this understudied malignancy.

cancer biology↗

bioRxiv2023

KDM6 demethylases mediate EWSR1-FLI1-driven oncogenic transformation in Ewing Sarcoma

Ewing Sarcoma (EwS) is an aggressive bone and soft tissue tumor driven by the fusion oncoprotein EWSR1-FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neo-enhancers in a permissive cellular context. Inhibition of the oncogene remains challenging and current efforts instead seek to exploit emergent epigenetic treatments targeting EWSR1-FLI1 cofactors. Here, stemming from the genome-wide redistribution of H3K27me3 upon expression of EWSR1-FLI1 in pediatric hMSC, we unravel the contribution of the H3K27me3 demethylases KDM6A and KDM6B in transcriptional activation at EWSR1-FLI1 enhancers. We found that KDM6A has a demethylase-independent role in recruiting the SWI/SNF member BRG1 at EWSR1-FLI1-primed enhancers containing single GGAA motif, which is critical for EwS tumor growth. Conversely, KDM6B demethylates H3K27me3 at EWSR1-FLI1-active enhancers containing multimeric GGAA repeats and its deletion synergizes with EZH2 inhibitors. Our results highlight KDM6 demethylases as EWSR1-FLI1 cofactors with potential for future targeted therapies.

cancer biology↗