SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma

Journal of Experimental & Clinical Cancer Research

Isabella Sperduti¹  Irene Terrenato¹  Rossella Loria²  Silvia Soddu²  Rita Falcioni²  Giulia Bon²  Valentina Laquintana³  Paolo Visca³  Virginia Ferraresi⁴  Chiara Bazzichetto⁴  Italia Falcone⁴  Rocco Fraioli⁵  Gianluca Bossi⁵  Marta Di Martile⁶  Valentina Caprara⁶  Donatella Del Bufalo⁶  Laura Rosanò⁶  Stefano Scalera⁷  Gennaro Ciliberto⁸  Michele Milella⁹ 

[1] Biostatistics and Bioinformatic Unit, Scientific Direction, IRCCS Regina Elena National Cancer Institute;Cellular Network and Molecular Therapeutic Target Unit, IRCCS Regina Elena National Cancer Institute;Department of Pathology, IRCCS Regina Elena National Cancer Institute;Division of Medical Oncology 1, IRCCS Regina Elena National Cancer Institute;Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute;Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute;SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute;Scientific Directorate, IRCCS Regina Elena National Cancer Institute;Section of Oncology, Department of Medicine, University of Verona and Verona University Hospital Trust (AOUI Verona);

关键词: Semaphorin SEMA6A;    Melanoma;    Dual BRAF/MEK inhibition;    Actin cytoskeleton remodeling;    YAP;    Tumor microenvironment;   

DOI  :  10.1186/s13046-022-02354-w

来源: DOAJ

【 摘 要 】

Abstract Background Despite the promise of dual BRAF/MEK inhibition as a therapy for BRAF-mutant (BRAF-mut) melanoma, heterogeneous responses have been observed in patients, thus predictors of benefit from therapy are needed. We have previously identified semaphorin 6A (SEMA6A) as a BRAF-mut-associated protein involved in actin cytoskeleton remodeling. The purpose of the present study is to dissect the role of SEMA6A in the biology of BRAF-mut melanoma, and to explore its predictive potential towards dual BRAF/MEK inhibition. Methods SEMA6A expression was assessed by immunohistochemistry in melanoma cohort RECI1 (N = 112) and its prognostic potential was investigated in BRAF-mut melanoma patients from DFCI and TCGA datasets (N = 258). The molecular mechanisms regulated by SEMA6A to sustain tumor aggressiveness and targeted therapy resistance were investigated in vitro by using BRAF-mut and BRAF-wt melanoma cell lines, an inducible SEMA6A silencing cell model and a microenvironment-mimicking fibroblasts-coculturing model. Finally, SEMA6A prediction of benefit from dual BRAF/MEK inhibition was investigated in melanoma cohort RECI2 (N = 14). Results Our results indicate higher protein expression of SEMA6A in BRAF-mut compared with BRAF-wt melanoma patients and show that SEMA6A is a prognostic indicator in BRAF-mut melanoma from TCGA and DFCI patients cohorts. In BRAF-mut melanoma cells, SEMA6A coordinates actin cytoskeleton remodeling by the RhoA-dependent activation of YAP and dual BRAF/MEK inhibition by dabrafenib+trametinib induces SEMA6A/RhoA/YAP axis. In microenvironment-mimicking co-culture condition, fibroblasts confer to melanoma cells a proliferative stimulus and protect them from targeted therapies, whereas SEMA6A depletion rescues the efficacy of dual BRAF/MEK inhibition. Finally, in BRAF-mut melanoma patients treated with dabrafenib+trametinib, high SEMA6A predicts shorter recurrence-free interval. Conclusions Overall, our results indicate that SEMA6A contributes to microenvironment-coordinated evasion of melanoma cells from dual BRAF/MEK inhibition and it might be a good candidate predictor of short-term benefit from dual BRAF/MEK inhibition.

【 授权许可】

Unknown