Rnd3 regulates lung cancer cell invasion and migration independently of ROCK1 signaling via alpha 5 integrin modulation

Here, we identify a novel signaling pathway in which Rnd3 regulates the metastatic potential of lung cancer cells. Understanding this pathway could be leveraged to target metastatic disease. Rnd3 regulates cellular processes commonly dysregulated in cancer, and altered Rnd3 expression has been linked to several cancer types. Here, we show lung adenocarcinoma patients expressing low levels of Rnd3 have significantly higher survival rates. To gain mechanistic insight into this correlation, we knocked down Rnd3 in lung adenocarcinoma A549 and H460 cell lines and patient-derived lung-to-brain metastasis (PDLBM) cell lines as a proxy for advanced disease. Depletion of Rnd3 expression decreases cell invasion and migration, two hallmarks of metastasis, independently of RhoA-ROCK1 signaling in both lung adenocarcinoma and PDLBM cell lines, indicating the involvement of a novel pathway. The expression of alpha 5 integrin was increased in Rnd3-depleted A549 cells, and knocking down alpha 5 integrin restored cell migration and invasion rates in A549 cells. Identification of a RhoA-ROCK1-independent mechanism by which Rnd3 modulates alpha 5 integrin expression to control cell migration and invasion provides new insights into the molecular basis of pro-malignant properties. These properties that drive the metastatic potential of lung adenocarcinoma may be exploited to target metastatic disease.