Novel Molecular Signaling Pathway Inhibits Lung Cancer Growth and Metastasis

A gene that had not been linked previously to lung cancer was found to be a critical component of a novel molecular signaling pathway that restricts lung cancer progression and metastasis.

Investigators at Northwestern University (Evanston, IL, USA) based the current study on emerging evidence that the neuronal guidance molecule SLIT played a role in tumor suppression, as SLIT-encoding genes were found to be inactivated in several types of cancer, including lung cancer. The SLIT gene produces the protein Slit, which in conjunction with the protein Robo (Roundabout) constitute a cell signaling pathway with many diverse functions including axon guidance and angiogenesis. Slit refers to a secreted protein which is most widely known as a repulsive axon guidance cue and Robo to its transmembrane protein receptor.

The investigators reported in the November 3, 2015, online edition of the Journal of Clinical Investigation that SLIT inhibited cancer cell migration by activating RhoA. RhoA (Ras homolog gene family, member A) is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. This protein is essential for the signaling function of the Rho GTPase complex.

The investigators found that myosin 9b (Myo9b) was a ROBO-interacting protein that suppressed RhoA activity in lung cancer cells. X-ray crystallography structural analyses revealed that the RhoGAP domain of Myo9b contained a unique patch that specifically recognized RhoA. The ROBO intracellular domain interacted with the Myo9b RhoGAP domain and inhibited its activity. Therefore, SLIT-dependent activation of RhoA was mediated by ROBO inhibition of Myo9b. In a mouse model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis.

In lung cancer cells, the intracellular domain (ICD) of ROBO directly interacted with the Myo9b RhoGAP domain and inhibited its activity. Thus, the negative regulation of Myo9b by SLIT/ROBO signaling in lung cancer cells activated RhoA and inhibited cell migration. Supporting this model, the data showed that SLIT inhibited lung tumor invasion and metastasis in a xenograft mouse model. Furthermore, Myo9b was highly expressed in human lung cancer tissues as compared with levels observed in the control samples. Consistently, increased Myo9b expression was associated with lymph node metastasis, advanced tumor stage, and poor patient survival.

These results implicate the existence of a previously unknown SLIT/ROBO/Myo9b/RhoA signaling pathway that inhibits cell migration and suppresses lung cancer metastasis.

“Elevated Myo9b expression is associated with fast lung cancer progression and poor prognosis,” said senior author Dr. Jane Wu, professor of neurology and psychiatry at Northwestern University. “These observations suggest the exciting possibility of developing Myo9b as a new biomarker for cancer, especially lung cancer. Our study provides new insights into the molecular and cellular mechanisms underlying lung cancer invasion and metastasis, a critical process that often leads to fatal consequence. Our data also provide a solid foundation for developing new diagnostic and therapeutic tools for lung cancer.”

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