Understanding and targeting MYC in angiosarcoma
| Angiosarcoma is a rare, aggressive malignant neoplasm of endothelial origin, frequently arising in previously irradiated tissues. In radiation-associated angiosarcoma (RAAS), focal amplification leads to marked overexpression of MYC, a bHLH LZ transcription factor that normally regulates proliferation, differentiation, and cellular stemness. How MYC overexpression drives endothelial tumor initiation, progression, dedifferentiation, and therapy resistance remains poorly defined. We developed an endothelial-specific, reversible, doxycycline inducible MYC overexpression genetically engineered mouse model (GEMM) in which MYC can be toggled on and off in the vascular lineage. MYC induction rapidly led to the development of pulmonary angiosarcoma that progressed from low- to high-grade and to dedifferentiated angiosarcoma with loss of endothelial markers (e.g., CD31, ERG) within approximately 6 weeks. MYC removal arrested tumor growth and restored endothelial identity, demonstrating strict MYC dependency and tumor intrinsic plasticity. Leveraging this model and complementary human RAAS systems, we will dissect MYC-driven transcriptional and chromatin reprogramming using single nucleus RNA/ATAC profiling and MYC/MAX cistrome profiling (e.g., CUT&RUN), and evaluate direct MYC targeted therapeutics (e.g., Omomyc/OMO 103) and strategies that modulate MYC dosage. These studies aim to define the mechanisms of MYC mediated angiosarcomagenesis and identify actionable vulnerabilities to guide clinical translation in RAAS and other MYC addicted cancers. |