C Barceló1, P Sisó1, I de la Rosa1, C Megino-Luque1,2, R Navaridas1, O Maiques3, I Urdanibia1, N Eritja1,2, X Soria4, M Potrony5,6, N Calbet-Llopart5,7, S Puig5,7, X Matías-Guiu2,8,9, R M Martí10,11, A Macià12,13. 1. Oncologic Pathology Group, University of Lleida, IRBLleida, Lleida, Spain. 2. Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. 3. Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK. 4. Department of Dermatology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain. 5. Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. 6. Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain. 7. Melanoma Unit, Dermatology Department, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain. 8. Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain. 9. Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, l'Hospitalet de Llobregat, Barcelona, Spain. 10. Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. marti@medicina.udl.cat. 11. Department of Dermatology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain. marti@medicina.udl.cat. 12. Oncologic Pathology Group, University of Lleida, IRBLleida, Lleida, Spain. amacia@irblleida.cat. 13. Pharmacology Unit, Department of Experimental Medicine, School of Medicine, University of Lleida, Lleida, Spain. amacia@irblleida.cat.
Abstract
BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.
BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.
Authors: Anna C Obenauf; Yilong Zou; Andrew L Ji; Sakari Vanharanta; Weiping Shu; Hubing Shi; Xiangju Kong; Marcus C Bosenberg; Thomas Wiesner; Neal Rosen; Roger S Lo; Joan Massagué Journal: Nature Date: 2015-03-25 Impact factor: 49.962
Authors: Peter Bankhead; Maurice B Loughrey; José A Fernández; Yvonne Dombrowski; Darragh G McArt; Philip D Dunne; Stephen McQuaid; Ronan T Gray; Liam J Murray; Helen G Coleman; Jacqueline A James; Manuel Salto-Tellez; Peter W Hamilton Journal: Sci Rep Date: 2017-12-04 Impact factor: 4.379
Authors: Carla Barceló; Pol Sisó; Oscar Maiques; Inés de la Rosa; Rosa M Martí; Anna Macià Journal: Cancers (Basel) Date: 2020-02-08 Impact factor: 6.639