Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition
Src activation in lipid rafts confers epithelial cells with invasive potential to escape from apical extrusion during cell competition
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DOI：
10.1016/j.cub.2022.06.038
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发表时间：
2022-08-22
期刊：
影响因子：
9.2
通讯作者：
Okada，Masato
中科院分区：
文献类型：
--
作者：
Kajiwara，Kentaro;Chen，Ping-Kuan;Okada，Masato
健康上皮组织内的异常/癌细胞会经历顶端挤压以防止癌变，尽管一旦癌变进展，它们就会获得侵袭能力。然而，癌细胞逃离顶端挤压并侵入周围组织的分子机制仍然难以捉摸。在这项研究中，我们展示了上皮细胞竞争过程中细胞命运转换的分子机制。我们发现，在上皮细胞层内的竞争过程中，Src 转化促进粘着斑的成熟和细胞外基质的降解。 Src 转化的细胞通过鞘脂/富含胆固醇的膜微域/脂筏内的 Src 激活而经历基底分层，而当 Src 位于脂筏之外时，它们被顶部挤出。对比表型的比较分析表明，基底分层需要通过脂筏激活 Src-STAT3-MMP 轴。含 CUB 结构域的蛋白 1 (CDCP1) 被鉴定为 Src 激活支架和脂筏中的 Met 调节因子，其过度表达可诱导基底分层。在肾癌模型中，CDCP1 通过 Met 激活激活 Src-STAT3-MMP 轴，从而促进上皮间质转化介导的侵袭行为。总体而言，这些结果表明，脂筏中 Src 信号的空间激活赋予上皮细胞对顶端挤压的抵抗力和侵袭潜力，从而促进癌发生。
Abnormal/cancerous cells within healthy epithelial tissues undergo apical extrusion to protect against carcinogenesis, although they acquire invasive capacity once carcinogenesis progresses. However, the molecular mechanisms by which cancer cells escape from apical extrusion and invade surrounding tissues remain elusive. In this study, we demonstrate a molecular mechanism for cell fate switching during epithelial cell competition. We found that during competition within epithelial cell layers, Src transformation promotes maturation of focal adhesions and degradation of extracellular matrix. Src-transformed cells underwent basal delamination by Src activation within sphingolipid/cholesterol-enriched membrane microdomains/lipid rafts, whereas they were apically extruded when Src was outside of lipid rafts. A comparative analysis of contrasting phenotypes revealed that activation of the Src-STAT3-MMP axis through lipid rafts was required for basal delamination. CUB-domain-containing protein 1 (CDCP1) was identified as an Src-activating scaffold and as a Met regulator in lipid rafts, and its overexpression induced basal delamination. In renal cancer models, CDCP1 promoted epithelial-mesenchymal transition-mediated invasive behavior by activating the Src-STAT3-MMP axis through Met activation. Overall, these results suggest that spatial activation of Src signaling in lipid rafts confers resistance to apical extrusion and invasive potential on epithelial cells to promote carcinogenesis.