Elucidation of amino acid adaptive sensor in cancer cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22553
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Osawa Tsuyoshi 東京大学, 先端科学技術研究センター, 特任准教授 (50567592)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: 腫瘍微小環境 / がん代謝 / アミノ酸 / アミノ酸欠乏 / オミクス統合解析

Outline of Final Research Achievements

The tumor microenvironment plays an important role in malignant transformation such as growth, metastasis and drug resistance of cancer cells. The purpose of this study was to identify adaptive sensors to amino acid deficiency in cancer cells, inhibition of which can be utilized for the development of novel cancer treatments. We conducted researches on (1) exploration of adaptive sensors for amino acid deficiency and (2) elucidation of the adaptive mechanism of cancer to amino acid deficiency. We identified glutamine and other amino acid-specifically induced genes, histone modifications (H3K4me3, H3K27ac), promoters, enhancers, and possible upstream regulators. We identified candidate of sensors and regulators that are essential for amino acid deficiency, such as transcription factors and amino acid transporters.

Free Research Field

がん代謝

Academic Significance and Societal Importance of the Research Achievements

近年、がん細胞はロイシンなどの必須アミノ酸をmTOR複合体を介したシグナル伝達系で感知することが知られている。一方、グルタミンなどのアミノ酸欠乏感知機構は未だ不明な点が多い。本研究は、独自の低栄養培養やアミノ酸培養系を作成し、各アミノ酸で特異的に発現誘導される遺伝子群やエピゲノム制御機構を同定、各アミノ酸における上流転写因子を同定など、がん細胞の新規アミノ酸欠乏アダプティブ機構が存在する可能性を見出した。本研究により、がん悪性化を促進する新しいアミノ酸欠乏の感知・適応システムやアミノ酸代謝異常に関わる代謝経路や遺伝子変動の解明が可能となり、今後、新規がん治療法への応用が期待できる。