School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Int J Biol Sci. 2024 Apr 8;20(7):2356-2369. doi: 10.7150/ijbs.86699. eCollection 2024.
Dysregulation of cancer cell motility is a key driver of invasion and metastasis. High dysadherin expression in cancer cells is correlated with invasion and metastasis. Here, we found the molecular mechanism by which dysadherin regulates the migration and invasion of colon cancer (CC). Comprehensive analysis using single-cell RNA sequencing data from CC patients revealed that high dysadherin expression in cells is linked to cell migration-related gene signatures. We confirmed that the deletion of dysadherin in tumor cells hindered local invasion and distant migration using tumor models. In this context, by performing cell morphological analysis, we found that aberrant cell migration resulted from impaired actin dynamics, focal adhesion turnover and protrusive structure formation upon dysadherin expression. Mechanistically, the activation of focal adhesion kinase (FAK) was observed in dysadherin-enriched cells. The dysadherin/FAK axis enhanced cell migration and invasion by activating the FAK downstream cascade, which includes the Rho family of small GTPases. Overall, this study illuminates the role of dysadherin in modulating cancer cell migration by forcing actin dynamics and protrusive structure formation via FAK signaling, indicating that targeting dysadherin may be a potential therapeutic strategy for CC patients.
癌细胞运动失调是侵袭和转移的关键驱动因素。癌细胞中黏附素表达失调与侵袭和转移相关。在这里，我们发现了黏附素调节结肠癌（CC）迁移和侵袭的分子机制。对 CC 患者的单细胞 RNA 测序数据进行综合分析表明，细胞中黏附素表达升高与与细胞迁移相关的基因特征有关。我们通过肿瘤模型证实，肿瘤细胞中黏附素的缺失会阻碍局部侵袭和远处迁移。在这种情况下，通过进行细胞形态分析，我们发现异常的细胞迁移是由于黏附素表达后肌动蛋白动力学、焦点黏附转化和突出结构形成受损所致。从机制上讲，在富含黏附素的细胞中观察到粘着斑激酶（FAK）的激活。黏附素/FAK 轴通过激活 FAK 下游级联反应，包括 Rho 家族的小 GTPases，增强细胞迁移和侵袭。总的来说，这项研究阐明了黏附素通过 FAK 信号迫使肌动蛋白动力学和突出结构形成来调节癌细胞迁移的作用，表明靶向黏附素可能是 CC 患者的一种潜在治疗策略。
