title: Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis.
abstract: 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 newex vivomouse 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 ofGpnmb, 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.
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Homme
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Rikuka
authors.initials: R
authors.lastname: Shimizu
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takazawa
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. takuro-ind@umin.net.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002465:Cell Movement; D005136:Eye Proteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D018234:Sarcoma, Alveolar Soft Part / Q000473:pathology*
chemical_list: C478539:Aspscr1 protein, mouse; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C484068:Tcfeb protein, mouse; C068486:Tcfe3 protein, mouse