The mechanisms of BMP-EGFR cross talk in colorectal organoids

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07942
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka University
• Principal Investigator: Jumpei Kondo 大阪大学, 大学院医学系研究科, 准教授 (80624593)
• Co-Investigator(Kenkyū-buntansha): 井上 正宏 京都大学, 医学研究科, 特定教授 (10342990)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 大腸癌 / EGFR / オルガノイド / BMP / LRIG1 / バイオマーカー

Outline of Final Research Achievements

The BMP pathway affects colorectal cancer (CRC) cells differently than normal cells, sometimes promoting tumor growth and other times suppressing it. We found that CRC cells reside in a BMP-rich environment. Inhibiting BMP with LDN193189 slows CRC organoid growth by reducing EGFR levels through LRIG1-mediated protein degradation. In CRC organoids, BMP inhibition induces LRIG1 expression, which correlates with growth suppression. Knocking down LRIG1 rescued LDN193189-mediated growth inhibition. Combining LDN193189 with trametinib, a MEK inhibitor, cooperatively inhibited CRC growth in vitro and in vivo. These results suggest that simultaneous BMP and MEK inhibition could be a promising CRC treatment. Studying LRIG1 induction and growth suppression in patient-derived organoids may help identify potential responders to this therapy.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

BMP阻害剤は良性疾患である炎症性貧血の治療薬として臨床試験が行われており、抗腫瘍薬よりも副作用は低レベルであると考えられる。このような薬剤が抗腫瘍薬の効果を増強する目的で用いることができれば、がん治療の選択肢は大きく広がる。今回の検討では、BMP阻害剤の効果が期待できる症例を選択する機能的バイオマーカーの開発も同時に進めることができたため、将来的に臨床試験を行う段階に至った場合も高い成功率が期待できる。