Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis
Another focus of our work is on the cellular and molecular mechanisms governing migration of different types of cells, including neurons and non-neuronal cells. Either insufficient or excessive cell migration has been associated with age-related diseases including neurodevelopmental disorders, immune deficiencies, inflammation, and cancer metastasis.
Emerging evidence indicates that the neuronal guidance molecule, Slit, plays a role in tumor suppression, as Slit-encoding genes are inactivated in several types of cancer, including lung cancer. However, it is remains unclear how Slit and Robo function in lung cancer. Our studies in the past few years have uncovered a previously unknown signal transduction pathway involving Slit-Robo-Myo9b-RhoA (Kong et al, 2015; Yi et al, 2016). Our data show that Slit inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a Robo-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. Our studies further demonstrate that the Robo intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, Slit-dependent activation of RhoA is mediated by Robo inhibition of Myo9b. In a murine model, Slit-expressing cancer cells (as compared to cancer cells in which Slit expression was silenced) had a decreased capacity for tumor formation and lung metastasis. Examination of human lung cancer samples and adjacent non-tumor tissues has revealed that Myo9b is upregulated in the majority of cancer samples. Moreover, elevated Myo9b expression is associated with lung cancer progression and poor prognosis. Together, our work has identified Myo9b as a novel player in lung cancer and as a Robo interacting protein in the newly defined Slit-Robo-Myo9b-RhoA signaling pathway that restricts lung cancer progression and metastasis (Kong et al, 2015; Yi et al, 2016). Furthermore, our study suggests that targeting this signaling pathway has potential as a diagnostic and therapeutic strategy for lung cancer.
Systematic investigation using an integrated multi-disciplinary approach will help us not only understand fundamental mechanisms controlling cell migration in multiple biological processes but also discover new diagnostic biomarkers as well as therapeutic targets for a range of human diseases involving dys-regulation of cell migration.