The role of activin combined with different gene mutations in colorectal cancer EMT

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15502
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: WANG DONG 金沢大学, ナノ生命科学研究所, 特任助教 (20842983)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: activin / driver gene mutation / colorectal cancer / partial EMT

Outline of Final Research Achievements

This project focuses on identifying genetic mutations that determine the outcome of TGFβ signaling. KrasG12D mutation protected organoid cells from activin A (TGFβ superfamily cytokine)-induced growth suppression by inhibiting p21 and p27 expression. Furthermore, Trp53R270H gain-of-function (GOF) mutation together with loss of wild-type Trp53 by loss of heterozygosity (LOH) promoted activin A-induced partial EMT and increased metastatic incidence. RNA sequencing analysis indicated that expression of Hmga2 was significantly upregulated in organoids with Trp53 GOF/LOH alterations. Importantly, loss of HMGA2 blocked activin A-induced partial EMT and metastasis in Trp53 GOF/LOH organoids. These results indicate that TP53 GOF/LOH is a key genetic state that primes for TGFβ family-induced partial EMT and malignant progression of colorectal cancer. Activin signaling may be an effective therapeutic target for colorectal cancer harboring TP53 GOF mutations.

Free Research Field

cancer biology

Academic Significance and Societal Importance of the Research Achievements

In this project, we clarified the function and mechanism of activin in colon cancer. The findings indicate that activin signaling may be an effective therapeutic target for colorectal cancer harboring TP53 GOF mutations and expand our knowledge about EMT mechanism.