Integrative proteomic analysis of PDX models to develop targeted therapies for colorectal cancer metastasis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Kinoshita Takashi 愛知県がんセンター(研究所), 分子診断TR分野, 研究員 (40467311)
• Co-Investigator(Kenkyū-buntansha): 細田 和貴 愛知県がんセンター(研究所), がん情報・対策研究分野, 研究員 (00728412) ; 田口 歩 愛知県がんセンター(研究所), 分子診断TR分野, 分野長 (50817567)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 大腸癌 / 転移 / in vivo selection / PDXモデル / プロテオミクス / 細胞表面タンパク質 / 術前化学放射線療法 / 血液バイオマーカー

Outline of Final Research Achievements

In this study, we conducted multi-omics profiling of primary CRC and metastatic CRC to elucidate molecular mechanisms involved in the development of metastasis. 1. Molecular characterization of mouse colorectal cancer cell lines with different metastatic potential identified AVIL as a potential therapeutic target in patients with metastatic CRC. We demonstrated regulation of AVIL expression by interferon signaling. In addition, we identified potential interaction between AVIL and a tyrosine phosphatase. 2. PDX models were successfully generated from 66 primary CRC tumors and 28 liver metastases. We performed omics analysis, particularly focusing on proteomics, in these PDX tumors, resulting in identification of molecular signatures associated with metastatic CRC. 3. We identified circulating VEGFR3 as a novel biomarker for predicting response to neoadjuvant chemoradiation in locally advanced rectal cancer through proteomic analysis of plasmas from a mouse model of rectal cancer.

Free Research Field

がん分子生物学

Academic Significance and Societal Importance of the Research Achievements

大腸癌の転移再発に関わる分子機構の解明に向けて、90例を超える大腸癌PDXライブラリなど大規模な生体材料基盤を整備し、また付随する多層オミクスデータ基盤も構築できた。本研究課題によって、大腸癌の新規転移関連分子AVILの同定や、局所進行直腸癌における新規術前化学放射線療法効果予測血液バイオマーカーVEGFR3の同定など、難治である転移性大腸癌に対する革新的な分子標的薬・バイオマーカー開発の基盤となる多くの情報が得られた。