June 9 2017
We would like to inform you that the 25th IRCMS Seminar has been scheduled as below. We would be pleased to see many of you participating in the seminar.
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.