[Alveolar Soft Part Sarcoma-The Angiogenic Mechanism Regulated by a Fusion Gene Product].

Alveolar soft part sarcoma(ASPS)is a rare malignant tumor whose origin is unidentified, arising from deep soft tissue and affecting adolescents and young adults. ASPS is characterized by its abundant vascular network forming alveolar structures, and demonstrates frequent hematogenous metastasis. An ASPSCR1-TFE3 fusion gene derived from t(X;17)chromosome translocation is detected as a disease gene in all cases, and the ASPSCR1-TFE3 protein causes abnormal transcriptional regulation. We generated a mouse model for ASPS by introducing ASPSCR1-TFE3 into mouse embryonic mesenchymal cells. In the model, tumor angiogenesis and alveolar structures of human ASPS were reproduced, revealing pericyte-rich blood vessels and metastatic processes with pericytic encapsulation of tumor cell nests. ASPSCR1-TFE3 is frequently associated with active enhancers and super-enhancers, and angiogenesis-related enhancers were significantly diminished by the loss of ASPSCR1- TFE3. Angiogenesis-associated enhancers and important target genes, Rab27a, Sytl2, Pdgfb and Vwf were identified by epigenetic CRISPR screening. Rab27a and Sytl2 facilitates trafficking of cytoplasmic vesicles containing angiogenic factors such as Pdgfb and Vwf, resulting in pericyte-rich vascular structures in ASPS. These studies highlight the importance of the Rab27/Sytl axis as a novel drug target in cancer.