Objective: 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 cellular embryonic origins and mimic the tissue-specific developmental programs. By combining in vivo analyses of connective tissue differentiation in mouse embryos, in vitro investigations of connective tissue cell plasticity during sarcomagenesis and state-of-the-art cell transcriptomic tools, we aim to comprehensively analyze neck musculoskeletal morphogenesis and identify key regulators of connective tissue specification, differentiation and malignancy.

Methods: Using the similarities between tumor and normal embryonic development, both characterized by rapid cell expansion, we 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. To characterize TGFβ function during morphogenesis and sarcomagenesis, we manipulate our candidate genes using both in vivo and in vitro models: (1) mouse embryos with conditional inactivation of TGFβR2 (main TGFβ receptor) in connective tissue precursors and (2) the fibrosarcoma (HT-1080) and undifferentiated pleomorphic sarcoma (U-2197) cell lines.

Results: Conditional inactivation of TGFβR2 in connective tissue precursors leads to disruptions in muscle patterning during development, indicating that TGFβ pathway plays a role in the interaction between connective tissue and muscle progenitors, which is essential for proper muscle patterning and musculoskeletal assembly. In HT-1080 and U-2197 cell lines,

a reduced expression of TGFβR2 affects clonogenic capacity of the tumor cells.

Conclusion: Our preliminary results suggest that TGFβ signaling affect cell regulation during both morphogenesis and tumorigenesis.