Volume-regulated Cl and oxidation-activated K channels in invasiveness and immunotherapy efficiency in human melanoma

Chloride and potassium ion channels involved in volume regulation likely play an important role in the invasiveness of melanoma cells and in the homing of T-lymphocytes, both processes related to cell migration and volume regulation. However the specific role of the newly discovered volume-regulating LRRC8 proteins forming the VRAC channel is unknown. In addition, we have identified a novel oxidation activated K channel, KROS, in human melanoma cells. The currents mediated by this channel are of extremely large amplitude and their role in melanoma is unknown. These findings open a new interesting perspective in the development of new strategies to target circulating tumor cells (CTC) to reduce their metastatic potential that is closely related to the ability to migrate. In the present project we plan to investigate the role of LRRC8 mediated VRAC channels and KROS channels in tumor invasiveness using as model a highly metastatic tumor such as melanoma. Since the role of the adaptive immune system is critical in the acquisition of an aggressive phenotype we have also included in our study the involvement of LRRC8 for the homing of T-lymphocytes. The overall idea of the present project is to obtain information on the role of LRRC8 and KROS in the processes of melanoma cell invasion and T-cell homing, and to target LRRC8 proteins developing synthetic peptides designed by computational studies to interfere with the capability of the cells to spread and invade.

Members:
Raffaella Barbieri
Paola Gavazzo
Cristiana Picco
Michael Pusch (Principal investigator)