Analysis of hematogenous metastasis mechanism using a mouse model for alveolar soft tissue sarcoma

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Tanaka Miwa 公益財団法人がん研究会, がん研究所 発がん研究部, 研究員 (70345883)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ASPL-TFE3 / 融合遺伝子 / 胞巣状軟部肉腫 / 骨軟部腫瘍 / 転移 / 血管新生 / MIT/TFEファミリー / マウスモデル

Outline of Final Research Achievements

Alveolar soft part sarcoma (ASPS) occurs mostly in young adults with frequent hematogenous metastasis even at the initial diagnosis. Our ASPS model showed prominent angiogenesis and vascular involvement, resulting in frequent lung metastasis. The lining of hemangiopericytes were characteristic in ASPS vasculature and on the surface of tumor emboli, suggesting that the protection by hemangiopericytes is important for the survival of ASPS’s circulating-tumor-cell. In addition, we identified Gpnmb that plays an important role in intravasation of ASPS tumor cells as a direct target of the ASPL-TFE3 fusion transcription factor. Enhanced localization of GPNMB at the front of tumor invasion and intravasation in both mouse and human ASPS were observed. To examine the oncogenic activity of ASPL fusion genes, artificial chimeric genes were generated consisting of the 5’ ASPL and 3’ MIT/TFE sequences. The ASPL-TFE3 and ASPL-TFEB but not ASPL-TFEC and ASPL-MITF induced sarcoma.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

希少がんである胞巣状軟部肉腫は、初診時にしばしば転移が指摘される若年者の肉腫である。マウスモデルの解析によって、転移の際には、肉腫細胞が血管でできた小さなカプセルに包まれた状態で血管内を移動していることが分かった。これは、宿主免疫からの回避法である可能性が考えられた。また、肉腫細胞が血管内に侵入する際には、原因遺伝子ASPL-TFE3(AT3)の標的であるGPNMBの発現が不可欠であることも見出した。さらに、肉腫の発症に必須なAT3の機能領域を絞り込むことができた。今後は、GPNMBが治療標的になり得るかどうかの検証と、AT3の発がん機能を制御するエピゲノム環境の解析を行う。