Sarcoma Analysis through Neck Development

ongoing

Head and neck sarcomas constitute rare malignant tumors of mesenchymal origin with poor prognosis. Rarity induces major challenges for diagnosis and limits the understanding of the molecular pathogenesis of sarcoma and its malignancy processes. Recent studies have demonstrated that tumor subsets share transcriptomic similarities with their corresponding cell lineage embryonic origins and mimic the tissue-specific developmental programs. We will combine developmental and cancer biology approaches and state-of-the-art cell transcriptomic tools to comprehensively analyze neck musculoskeletal morphogenesis and identify regulators of mesenchymal malignancy. Using the similarities between tumor and normal embryonic development, both characterized by rapid cell expansion, we will investigate embryonic pathways that could be re-initiated during tumor formation and expansion. TGFβ signaling appears critical for both tumorigenesis and neck musculoskeletal formation by modulating genetic networks involved in cell proliferation and differentiation. Manipulation of our candidate genes in sarcoma cell lines and mouse embryo will characterize TGFβ function during morphogenesis and sarcomagenesis and assess how TGFβ pathway dysregulation is associated with disease progression and treatment responsiveness. Transcriptomic sequencing at single cell level of the heterogenous neck connective tissue precursors will generate the first single-cell atlas of the developing neck. Comparison of developmental dataset with published single-cell sequencing dataset from sarcoma primary tumors and surrounding healthy tissues will allow us to identify molecular processes of normal and tumor development to uncover developmental programs associated with sarcoma induction. The collected data will allow a better understanding of the mechanisms behind TGFβ regulation and neck sarcomagenesis, and will hopefully uncover novel and targetable components for tumor treatments.