Molecular dissection of malfunction of cell competition-mediated elimination of transformed cells in intestine

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03166
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 42030:Animal life science-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Kon Shunsuke 東京理科大学, 研究推進機構生命医科学研究所, 講師 (70506641)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 細胞競合 / 多段階発がん / NF-κB / MMP21

Outline of Final Research Achievements

Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. In this study, we examine the effect of sequential accumulation of gene mutations, mimicking multi-sequential carcinogenesis on RasV12-induced cell competition in intestinal epithelial tissues. Consequently, we find that directionality of RasV12-cell extrusion in Wnt-activated epithelia is reversed, and transformed cells are delaminated into the basal lamina via non-cell autonomous MMP21 upregulation. Subsequently, diffusively infiltrating, transformed cells develop into highly invasive carcinomas. Elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. Collectively, this study shows that cells with high mutational burdens exploit cell competition for their benefit by behaving as unfit cells, endowing them with an invasion advantage.

Free Research Field

がん生物学

Academic Significance and Societal Importance of the Research Achievements

細胞競合は、正常上皮細胞が担う抗腫瘍機能として注目を浴びている。しかしながら、個体が実際に発がんに至る過程において、細胞競合の機能がどのように変容するかはよく分かっていない。本研究では、ヒト家族性大腸がんで好発するAPC→Rasの変異蓄積をマウスにて再現したところ、細胞競合によって本来管腔へと排除されるべき変異細胞の一部が、基底膜側へとびまん性に浸潤することを見出し、その分子論的メカニズムの一端を明らかにした。この研究成果より、複数の遺伝子変異が蓄積した変異細胞は細胞競合現象を利用することにより基底膜浸潤すること、またこのプロセスに関わる分子が新たながん治療標的となり得ることが期待される。