New Insights on the Signaling Hub that Drives Cancer Metastasis

A University of Hawaii (UH) Cancer Center researcher has identified how some cancer cells are made to move during metastasis. The research provides a better understanding of how cancer spreads and may create new opportunities for cancer drug development.

Joe W. Ramos, Ph.D., deputy director of the UH Cancer Center and collaborators focused on investigating how oncogenes and related signals lead to dysregulation of normal processes within the cell and activate highly mobile and invasive cancer cell behavior. They published their study, “RSK2 Drives Cell Motility by Serine Phosphorylation of LARG and Activation of Rho GTPases,” in the Proceedings of the National Academy of Sciences (PNAS).

“Directed migration is essential for cell motility in many processes, including development and cancer cell invasion. RSKs (p90 ribosomal S6 kinases) have emerged as central regulators of cell migration; however, the mechanisms mediating RSK-dependent motility remain incompletely understood. We have identified a unique signaling mechanism by which RSK2 promotes cell motility through leukemia-associated RhoGEF (LARG)-dependent Rho GTPase activation. RSK2 directly interacts with LARG and nucleotide-bound Rho isoforms, but not Rac1 or Cdc42,” write the investigators.

“We further show that epidermal growth factor or FBS stimulation induces association of endogenous RSK2 with LARG and LARG with RhoA. In response to these stimuli, RSK2 phosphorylates LARG at Ser1288 and thereby activates RhoA. Phosphorylation of RSK2 at threonine 577 is essential for activation of LARG-RhoA. Moreover, RSK2-mediated motility signaling depends on RhoA and -B, but not RhoC. These results establish a unique RSK2-dependent LARG-RhoA signaling module as a central organizer of directed cell migration and invasion.”

The researchers described a mechanism in which oncogenes turn on the RSK2 protein that is required for cancer cells to move. Dr. Ramos and colleagues found that the RSK2 protein forms a signaling hub that includes the LARG and RhoA proteins. Turning on this signaling hub activates the movement of cancer cells. These results significantly advance understanding of how cancer cells are made to move during metastasis and may provide more precise targets for drugs to stop cancer metastasis in patients where there are oncogenic mutations, according to Dr. Ramos.

“Blocking cancer invasion and metastasis remains a central challenge in treating patients. We anticipate that this research may lead to new therapeutic opportunities for brain tumors, melanoma, and breast cancer among others. We are currently focused on these opportunities and developing new compounds to target this signaling hub,” he said.