We performed a high-throughput whole-genome RNAi screen to identify novel inhibitors of ciliogenesis in normal and basal breast cancer cells. Our screen uncovered a previously undisclosed, extensive network of genes linking integrin signaling and cellular adhesion to the extracellular matrix with inhibition of ciliation in both normal and cancer cells. Surprisingly, a cohort of genes encoding extracellular matrix (ECM) proteins was also identified. We characterized several ciliation inhibitory genes and showed that their silencing was accompanied by altered cytoskeletal organization and induction of ciliation, which restricts cell growth and migration in normal and breast cancer cells. Conversely, supplying an integrin ligand, vitronectin, to the ECM rescued the enhanced ciliation observed upon silencing this gene. Aberrant ciliation could also be suppressed through hyper-activation of the YAP/TAZ pathway, indicating a potential mechanistic basis for our findings. Our findings suggest an unanticipated reciprocal relationship between ciliation and cellular adhesion to the extracellular matrix and provide a resource that could vastly expand our understanding of controls involving “outside-in” and “inside-out” signaling that restrain cilium assembly.

我们进行了高通量全基因组 RNAi 筛选，以鉴定正常和基底乳腺癌细胞中纤毛发生的新型抑制剂。我们的筛选发现了一个先前未公开的广泛基因网络，该网络将整合素信号传导和细胞粘附到细胞外基质与抑制正常细胞和癌细胞的纤毛化联系起来。令人惊讶的是，还鉴定了一组编码细胞外基质 (ECM) 蛋白的基因。我们表征了几种纤毛抑制基因，并表明它们的沉默伴随着细胞骨架组织的改变和纤毛的诱导，这限制了正常和乳腺癌细胞中的细胞生长和迁移。相反，向 ECM 提供整合素配体玻连蛋白可以挽救在沉默该基因时观察到的纤毛增强。异常纤毛也可以通过 YAP/TAZ 通路的过度激活来抑制，这表明我们的研究结果具有潜在的机制基础。我们的研究结果表明纤毛和细胞与细胞外基质的粘附之间存在意想不到的相互关系，并提供了一种资源，可以极大地扩展我们对涉及“由外到内”和“由内向外”信号传导的控制的理解，这些信号限制了纤毛组装。