25th IRCMS Seminar

June 9 2017

We had a large number of participants come to the 25th IRCMS Seminar held on June 9, for which we would like to express our gratitude.

Date:   June 9, 2017 (Fri)      Time:  16:00 - 17:00

Venue:  2F Seminar Room, Center for AIDS Research (CAIDS)  

Speaker: Eishu Hirata, M.D.,Ph.D.

Senior Assistant Professor, Department of Oncologic Pathology, Kanazawa Medical University

"Imaging 'Failure'  How BRAF inhibition generates drug tolerant microenvironments"

Intravital imaging of BRAF-mutant melanoma cells containing an ERK/MAPK biosensor reveals how the tumor microenvironment affects response to BRAF inhibition by PLX4720. Initially, melanoma cells respond to PLX4720, but rapid reactivation of ERK/MAPK is observed in areas of high stromal density. This is linked to ''paradoxical'' activation of melanoma-associated fibroblasts by PLX4720 and the promotion of matrix production and remodeling leading to elevated integrin β1/FAK/Src signaling in melanoma cells. Fibronectin-rich matrices with 3-12 kPa elastic modulus are sufficient to provide PLX4720 tolerance. Co-inhibition of BRAF and FAK abolished ERK reactivation and led to more effective control of BRAF-mutant melanoma. We propose that paradoxically activated MAFs provide a ''safe haven'' for melanoma cells to tolerate BRAF inhibition.