Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway

Normal epithelial cells exert their competitive advantage over RasV12-transformed cells and eliminate them into the apical lumen via cell competition. However, the internal or external factors that compromise cell competition and provoke carcinogenesis remain unknown. 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 the 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. The elevated production of MMP21 is elicited partly through NF-κB signaling, blockage of which restores apical elimination of RasV12 cells. We further demonstrate that the NF-κB-MMP21 axis is significantly bolstered in early colorectal carcinoma in humans. 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.正常上皮细胞可通过细胞竞争（cell competition）获得相较于RasV12转化细胞的竞争优势，并将后者清除至顶腔。然而，目前尚不清楚哪些内、外因素会削弱细胞竞争并诱发癌变。本研究模拟多阶段癌变进程，探究基因突变的序贯积累对肠上皮组织中RasV12诱导的细胞竞争的影响。研究结果显示，在Wnt激活的上皮组织中，RasV12细胞的挤出方向发生逆转；转化细胞经非细胞自主性的MMP21（基质金属蛋白酶21，matrix metalloproteinase 21）上调作用，脱离上皮层并迁移至基膜。随后，弥散浸润的转化细胞会发展为高侵袭性癌。MMP21的表达上调部分由NF-κB（核因子κB）信号通路介导，阻断该通路即可恢复RasV12细胞的顶腔清除过程。本研究进一步证实，在人类早期结直肠癌组织中，NF-κB-MMP21信号轴的活性显著增强。综上，本研究表明，具有高突变负荷的细胞可通过模拟不适宜细胞的表型，利用细胞竞争为自身牟利，进而获得侵袭优势。