Biology subjects

Taboas, P.

Publications and source records attributed to Taboas, P..

3 recordsLinked to original sources

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

Targeting CXADR-mediated AKT signaling suppresses tumorigenesis and enhances chemotherapy efficacy in Ewing sarcoma

Distant metastasis is the leading cause of mortality in Ewing sarcoma (EwS) - a malignant bone or soft-tissue cancer mainly affecting children, adolescents, and young adults. Despite continuous efforts in understanding its pathogenesis, the molecular mechanisms driving EwS metastasis remain poorly understood, thus limiting the potential for therapeutic progress. Here, we identify the tight junction component Coxsackievirus and Adenovirus receptor (CXADR) as a critical regulator of cancer progression and metastasis in EwS. Differential gene expression analysis of patient tumors from two independent cohorts revealed that elevated CXADR levels are associated with metastatic disease and poor overall survival. In functional experiments, conditional CXADR knockdown reduced the growth of EwS cell line models in vitro, and suppressed local tumorigenesis. Notably, CXADR knockdown completely abrogated metastasis formation in vivo. Integration of transcriptome profiling and mechanistic studies uncovered that CXADR promotes the activation of AKT signaling, likely through complex formation with PTEN. Consequently, pharmacological targeting of AKT using the FDA-approved pan-AKT inhibitor Capivasertib showed CXADR-dependent cytotoxicity, with enhanced efficacy if combined with the EwS standard-of-care chemotherapeutic agent Vincristine. Collectively, our findings establish CXADR as a prognostic and predictive biomarker in EwS, highlighting AKT inhibition combined with chemotherapy as a promising strategy for patients with high CXADR expression. Together, these findings support a precision medicine approach combining molecular stratification and targeted therapies to improve patient outcomes in metastatic EwS.

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↗