Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis.

Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Rikuka Shimizu, Yutaka Takazawa, Takuro Nakamura

Cancer research 2017 Feb 15

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Alveolar soft part sarcoma (ASPS) is a slowly growing, but highly metastatic, sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here, we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. High expression of glycoprotein nmb (GPNMB), a transcriptional target of ASPSCR1-TFE3, was observed at the sites of intravasation. ASPS tumor cells also demonstrated enhanced transendothelial migration activity, which was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, a key step in cancer metastasis. The present model also enabled the evaluation of TFE/MITF family transcription factor function, which demonstrated that ASPSCR1-TFEB possessed definitive albeit less marked oncogenic activity than that of ASPSCR1-TFE3. Collectively, our mouse model provides a tool to understand oncogenic, angiogenic, and metastatic mechanisms of ASPS. It also identifies important motifs within the ASPSCR1-TFE3 fusion protein and provides a platform for developing novel therapeutic strategies for this disorder. Cancer Res; 77(4); 897-907. ©2016 AACR. ©2016 American Association for Cancer Research.

Citation

Miwa Tanaka, Mizuki Homme, Yukari Yamazaki, Rikuka Shimizu, Yutaka Takazawa, Takuro Nakamura. Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis. Cancer research. 2017 Feb 15;77(4):897-907