Real-time imaging and PDX based treatment strategy for poor-prognosis mesenchymal-type colorectal cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16313
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Okayama University
• Principal Investigator: Yano Shuya 岡山大学, 大学病院, 助教 (50794624)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 大腸癌 / 上皮間葉転換 / 分子イメージング / 患者由来腫瘍組織片

Outline of Final Research Achievements

The latest subtypes of colorectal cancer (CRC) indicates that mesenchymal-type (M-type) CRC has the poorest prognosis. M-type CRC cells has epithelial-mesenchymal plasticity (EMP). However, it is difficult to monitor in real time dynamic EMP. Here, using a reversible EMT-MET biosensor, we demonstrated that only M-type CRC has instinct EMP. Time-lapse real-time imaging demonstrated M-type CRC cells survive chemotherapy and then they returned to E-state after cessation of chemotherapy. In contrast, inhibition of EMP by EMT inhibitors sensitized M-type CRC cells to chemotherapy. Furthermore, patient-derived xenograft (PDX) from M-type CRC also had EMP, which worked during chemotherapy. In contrast, EMP of PDX was easily inhibited by EMT inhibitors. Thus, real-time imaging and PDX model indicates that inhibition of EMP of is an Achilles’ heel for poor-prognosis M-type CRC, thus would be one of the most effective strategies for precision medicine.

Free Research Field

癌の分子イメージング

Academic Significance and Societal Importance of the Research Achievements

世界的な大腸癌の遺伝子変異、遺伝子発現により分子サブタイプは決定したが、予後不良間葉型大腸癌に対し期待されたほど治療戦略は定まらなかった。これは保存された試料だけでは間葉型大腸癌の本態に迫れないからである。これらを克服するため、EMTイメージングを用いた動的な解析と患者由来組織片(PDX)マウスモデルで実際の臨床を模倣した独自な評価モデルを構築した。我々のイメージング技術とPDXモデルを用いると、予後不良間葉型大腸癌は殺細胞剤では逆にEMTを惹起して抵抗性になるため、EMT阻害薬と殺細胞剤の併用療法が新しい治療戦略となることが示された。また、この解析系は他臓器固形腫瘍にも応用可能である。