PDF(Pubmed)
Abstract：
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 in vivo 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.
摘要：
癌细胞运动失调是侵袭和转移的关键驱动因素。在癌细胞中的高表达与侵袭和转移相关。这里,我们发现了Dhadherin调节结肠癌（CC）迁移和侵袭的分子机制。使用来自CC患者的单细胞RNA测序数据进行的综合分析显示，细胞中的高调差凝集素表达与细胞迁移相关的基因签名有关。我们证实，使用体内肿瘤模型，肿瘤细胞中弱粘附素的缺失阻碍了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受损的肌动蛋白动力学引起的，粘附素表达后的粘着斑周转和突出结构形成。机械上,在富含dysadherin的细胞中观察到粘着斑激酶（FAK）的激活。dhadherin/FAK轴通过激活FAK下游级联增强细胞迁移和侵袭，其中包括Rho家族的小型GTPases。总的来说,本研究通过FAK信号迫使肌动蛋白动力学和突出结构形成，阐明了调变蛋白在调节癌细胞迁移中的作用，这表明靶向调黑素可能是CC患者的潜在治疗策略。
