Biology subjects

Tirode, F.

Publications and source records attributed to Tirode, F..

7 recordsLinked to original sources

bioRxiv2026

Redundant roles of YES and SRC tyrosine kinases in driving malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas that are largely incurable with no clinically effective systemic therapies or immunotherapies for advanced disease. Here, we identify the SRC-family kinases (SFKs) YES and SRC as redundant, essential drivers of MPNST growth. Dual inhibition of YES/SRC activity by genetic silencing or pharmacological SFK inhibitors markedly suppressed the proliferation of multiple NF1-mutant MPNST cell lines. In vivo, conditional genetic depletion of YES/SRC in MPNST cells abrogated tumor growth in subcutaneous and orthotopic models, and dasatinib treatment delayed tumor progression and improved overall survival. Integrated transcriptomic and phosphotyrosine proteomic analyses revealed that YES/SRC inactivation extensively rewires MPNST signaling, coordinately repressing multiple oncogenic signaling pathways and downstream cell cycle transcriptional programs. Unexpectedly, YES/SRC inhibition also upregulated interferon and antigen processing and presentation pathways and increased cell-surface MHC class I expression, consistent with tumor-intrinsic immune reactivation. Clinically, analysis of a large sarcoma cohort demonstrated that YES1 is significantly overexpressed in MPNST compared to benign soft tissue tumors. Collectively, our findings establish YES/SRC as non-oncogene vulnerabilities in MPNST.

cancer biology↗

bioRxiv2026

Alternative Lengthening of Telomeres and CINSARC are interconnected toward non-translocation-related sarcomas progression

Alternative lengthening of telomeres (ALT) is a telomere elongation mechanism activated during oncogenesis and primarily acting in tumors of mesenchymal origin. Although the proteins involved in the machinery enabling ALT to elongate telomeres are becoming better understood, the underlying biology of this mechanism remains unclear. In the present study, we took advantage of a fully characterized cohort of 98 leiomyosarcomas (LMS) from the French Sarcoma Group to further our understanding of the ALT mechanism. We first compared the transcriptomic profiles of ALT+ and TERT+ LMS and demonstrated a strong enrichment of the CINSARC signature in ALT+ tumors. The establishment of an ALT+-related signature in these LMS confirmed the close association between CINSARC and ALT in two additional cohorts of non-translocation-related sarcomas. In vitro mesenchymal models of spontaneous ALT induction showed increased CINSARC expression following acquisition of the ALT mechanism. Conversely, ALT inactivation, through BLM inhibition, led to decreased CINSARC expression. These results establish CINSARC as a new hallmark of the ALT mechanism in non-translocation-related sarcomas and demonstrate the association of a cellular biological process with the CINSARC prognostic signature, namely the ALT mechanism.

cancer biology↗

bioRxiv2026

Spatially resolved diversity in molecular states underlies congenital melanocytic nevi and associated tumors

The congenital melanocytic nevus (CMN) is a developmental skin disorder characterized by prenatal melanocyte overgrowth, exhibiting heterogeneity in surface size, depth, and clinical behavior. Large/giant CMN carry an elevated, anticipatory melanoma risk relative to more common, small CMN. However, deeper insights into melanocytic states, genomic and epigenomic alterations, and microenvironmental cues governing disease progression are needed to predict lesions disposed to transformation. Although large/giant CMN melanocyte heterogeneity was recently established, spatial organization of these states and their niche interactions are unknown. Using advanced spatial and single-cell transcriptomics and bulk methylomics, we characterized ten CMN, seven CMN-associated proliferative nodules and three clinically diagnosed melanomas arising in CMN from children, integrating data from healthy skin references to contextualize melanocyte states in situ. CMN-specific melanocytic states, distinct in differentiation and proliferation, were spatially stratified, with immature melanocytes in deep dermis and more differentiated melanocytes approaching the epidermis. We then constructed a robust atlas of CMN cellular states by integrating single-cell transcriptomic data from five new large/giant CMN with published datasets, using it to deconvolute the spatial information. Cell-cell communication inference uncovered enhanced signaling (e.g. pleiotrophin, IGF1, periostin, semaphorin pathways) between CMN melanocytes, fibroblasts, and hair follicle-associated cells. Analysis of CMN-derived tumors, including longitudinal cases with [≥]2 samples, revealed divergent spatial melanocytic transcription distinguishing immune-enriched lesions from tumors with oncogenic/pro-invasive signatures. Collectively, these findings establish a spatially resolved framework linking melanocyte heterogeneity, signaling, and genomic instability in CMN, providing mechanistic insights to refine risk stratification and prognosis for CMN-associated tumors.

genetics↗

bioRxiv2025

SRF fusion oncogenes encode constitutively activated chimeric transcription factors in myoid soft tissue tumors

SRF fusion genes drive the pathogenesis of muscle-related soft tissue tumors, including subsets of perivascular tumors, inflammatory myofibroblastic tumor, and rhabdomyosarcoma. SRF encodes Serum Response Factor, a well-characterized transcription factor that regulates muscle development. We characterized four fusion genes: SRF::RELA, SRF::FOXO1, SRF::ICA1L, and SRF::PDGFRB. All localized to the nucleus and dimerized through the SRF MADS box. SRF::RELA, SRF::FOXO1, and SRF::ICA1L acted as constitutively active transcription factors independent of canonical cofactors, binding SRF target promoters and driving transcription via the partner transactivation domain (TAD). A cryptic TAD was uncovered in ICA1L. These fusions promoted mesenchymal cell growth and upregulated muscle-related genes in mesenchymal stem cells, recapitulating transcriptional signatures of human tumors. In contrast, SRF::PDGFRB acted through its kinase domain, was imatinib-sensitive, activated STAT1 and stimulated inflammation genes, consistent with its tumor phenotype. SRF fusions thus define a novel family of oncogenes in human myoid soft tissue tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/676997v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@621647org.highwire.dtl.DTLVardef@1a496b1org.highwire.dtl.DTLVardef@a1643corg.highwire.dtl.DTLVardef@1bbca8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Clinical sequencing efforts are uncovering numerous fusion genes in childhood solid tumors, yet few methods exist to delineate fusion-oncogenes from structural changes of unknown significance. One such novel fusion gene is VGLL2-NCOA2, which was described by us and others in patients with congenital sarcomas but has lacked functional validation. To determine if this fusion is an oncogene, and how it is driving disease, we developed a vertebrate zebrafish model and mouse allograft model of human VGLL2-NCOA2 driven sarcomagenesis. We found that VGLL2-NCOA2 is indeed an oncogene and is sufficient to generate mesenchymal tumors that recapitulate the human disease at the histological and transcriptional level. Zebrafish VGLL2-NCOA2 tumors display features of arrested skeletal muscle development, and a subset transcriptionally cluster with somitogenesis in developing embryos. By comparing tumor and embryonic gene expression signatures, we identified developmentally regulated targets that VGLL2-NCOA2 potentially leverages for tumorigenesis. These targets highlight the core biology of the disease and could represent therapeutic opportunities. Specifically, a RAS family GTPase, arf6/ARF6, involved in actin remodeling and rapid cycling of endocytic vesicles at the plasma membrane, is highly expressed during zebrafish somitogenesis and in VGLL2-NCOA2 tumors. In zebrafish tumors, arf6 protein is highly expressed and is absent from mature skeletal muscle. In VGLL2-NCOA2 mouse allograft models and patient tumors, ARF6 mRNA is overexpressed as compared to skeletal muscle or normal controls. More broadly, ARF6 is overexpressed in adult and pediatric sarcoma subtypes as compared to mature skeletal muscle. Overall, our cross-species comparative oncology approach provides evidence that VGLL2-NCOA2 is an oncogene which leverages developmental programs for tumorigenesis, and that one of these programs, the reactivation or persistence of arf6/ARF6, could represent a therapeutic opportunity.

cancer biology↗

bioRxiv2019

Transcriptional programs define intratumoral heterogeneity of Ewing sarcoma at single cell resolution

EWSR1-FLI1, the chimeric oncogene specific for Ewing sarcoma (EwS), induces a cascade of signaling events leading to cell transformation. However, it remains elusive how genetically homogeneous EwS cells can drive heterogeneity of transcriptional programs. Here, we combined independent component analysis of single cell RNA-sequencing data from diverse cell types and model systems with time-resolved mapping of EWSR1-FLI1 binding sites and of open chromatin regions to characterize dynamic cellular processes associated with EWSR1-FLI1 activity. We thus defined an exquisitely specific and direct, super-enhancer-driven EWSR1-FLI1 program. In EwS tumors, cell proliferation was associated with a well-defined range of EWSR1-FLI1 activity; moreover, cells with a high EWSR1-FLI1 activity presented a strong oxidative phosphorylation metabolism. In contrast, a subpopulation of cells from below and above optimal EWSR1-FLI1 activity was characterized by increased hypoxia. Overall, our study reveals sources of intratumoral heterogeneity within Ewing tumors.

cancer biology↗

bioRxiv2019

CIC-DUX4 expression drives the development of small round cell sarcoma in transgenic zebrafish: a new model revealing a role for ETV4 in CIC-mediated sarcomagenesis

CIC-DUX4 sarcoma is a rare subtype of sarcoma characterized by a devastating prognosis and resistance to conventional therapeutic strategies. So far, only few models of the disease have been reported, and its biological mechanisms remain to be elucidated. We established mosaic transgenic zebrafish expressing the human CIC-DUX4 fusion under the control of the {beta}-actin promoter. CIC-DUX4 transgenic fish rapidly developed aggressive soft tissue tumors with a high penetrance. RNAseq profiling revealed that fish tumors shared major common targets with human tumors and cell lines, including the overexpression of the Pea3 transcription factors, etv4 and etv5. Tumor development was strongly impaired in etv4-deficient zebrafish, implicating Etv4 as a critical effector of CIC-DUX4-mediated oncogenesis. Altogether, we report here the first in vivo model of CIC-DUX4 sarcoma in zebrafish, which will represent a major tool for future preclinical research.

cancer biology↗