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Translational Therapeutics

M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors

British Journal of Cancer volume 127, pages 1142–1152 (2022)Cite this article

Subjects

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.

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Fig. 1: Secreted media from Vemurafenib-resistant melanoma cell lines induces a resistance phenotype in sensitive melanoma cells.
Fig. 2: Cytokine secretome profile of Vemurafenib-resistant melanoma cell lines exhibit an increase in pro-tumour cytokines.
Fig. 3: M-CSF promotes the acquisition of Vemurafenib-resistance in BRAFV600E melanoma cells.
Fig. 4: Autophagic blockers Mibefradil/Chloroquine, Vemurafenib and M-CSF mAb-combined therapy induce apoptotic cell death and impair migration of BRAFV600E-resistant melanoma cells.
Fig. 5: Autophagic blockers Mibefradil/Chloroquine, Vemurafenib and M-CSF mAb-combined therapy reduce tumour growth and vascularisation of BRAFV600E-resistant melanoma cells
Fig. 6: M-CSF plasma levels determine melanoma OS and DFS in metastatic melanoma patients.

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Acknowledgements

This work was supported by grants from ISCIII/FEDER “Una manera de hacer Europa” (PI1500711 to R.M.M. & PI18/00573 to RMM & AM and PI20/00502 to NE) and CIBERONC-CB16/12/00231 to XMG, Fundació la Marató de TV3 (FMTV 201331-31) to RM and Generalitat de Catalunya (2014/SGR138) to XMG. CB and PS hold a predoctoral fellowship from UdL-IRBLleida. IR holds a predoctoral fellowship from AECC. AM holds a postdoctoral fellowship from AECC. The cell culture experiments were performed in the Cell Culture Scientific & Technical Service from Universitat de Lleida (UdL), Lleida, Spain. Work supported by the Xarxa de Bancs de Tumours de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC)”, IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS (PT17/0015/0027; PT20/00021) and HCB-IDIBAPS Biobank (R120904-090) integrated in the Spanish National Biobank Network (ISCIII Code C 0.000.334). The research at the Melanoma Unit from Hospital Clinic of Barcelona was partially funded by Insituto de Salud Carlos III (ISCIII), Spain, through projects PI18/00419 and PI18/01077, and co-funded by the European Union; by the grant AC16/00081, integrated in the Plan Estatal I + D + I, IMMUSPHINX-Transcan-2; by the CIBER de Enfermedades Raras of ISCIII, Spain, cofinanced by European Development Regional Fund “A way to achieve Europe” ERDF; and by the Generalitat de Catalunya (AGAUR 2017/SGR1134 and CERCA Program). We are grateful to our patients and relatives, to physicians and nurses from the Melanoma Unit of Hospital Clínic of Barcelona for collecting patients samples and data, and to Judit Mateu from the “Melanoma: image, genetics and immunology” group at IDIBAPS for her technical assistance. NCL holds a predoctoral fellowship from Ministerio de Educación, Cultura y Deportes, Spain (FPU17/05453).

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Author notes

  1. These authors contributed equally: C. Barceló, P. Sisó.

  2. These authors jointly supervised this work: R. M. Martí, A. Macià.

Authors and Affiliations

  1. Oncologic Pathology Group, University of Lleida, IRBLleida, Lleida, Spain

    C. Barceló, P. Sisó, I. de la Rosa, C. Megino-Luque, R. Navaridas, I. Urdanibia, N. Eritja & A. Macià

  2. Centre of Biomedical Research on Cancer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    C. Megino-Luque, N. Eritja, X. Matías-Guiu & R. M. Martí

  3. Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK

    O. Maiques

  4. Department of Dermatology, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain

    X. Soria & R. M. Martí

  5. Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain

    M. Potrony, N. Calbet-Llopart & S. Puig

  6. Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain

    M. Potrony

  7. Melanoma Unit, Dermatology Department, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain

    N. Calbet-Llopart & S. Puig

  8. Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain

    X. Matías-Guiu

  9. Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, l’Hospitalet de Llobregat, Barcelona, Spain

    X. Matías-Guiu

  10. Pharmacology Unit, Department of Experimental Medicine, School of Medicine, University of Lleida, Lleida, Spain

    A. Macià

Authors
  1. C. Barceló
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  2. P. Sisó
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  3. I. de la Rosa
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Contributions

Conceptualisation: CB, PS, RM, AM; Data curation: CB, PS, IR, CM, RN, OM, IU, NE, XS, AM; Formal analysis: CB, PS, OM, AM; Funding acquisition: RM, AM, SP, XMG, NE; Investigation: CB, PS, IR, CM, RN, OM, IU, NE, MP, NCLl, AM. Methodology: CB, PS, OM, AM. Project administration: CB, PS, AM. Resources: SP, MP, NCLl, XMG, NE, RM, AM; Software: CB, PS, OM. Supervision: RM, AM; Validation: CB, PS; Visualisation: CB, PS, AM; Writing—original draft preparation: CB, PS, AM; Writing—review and editing: CB, PS, OM, SP, RM, AM.

Corresponding authors

Correspondence to R. M. Martí or A. Macià.

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The animal experimental committee approved animal work procedures (CEEA from University of Lleida). The Clinical Research Ethics Committee of the HCB (study registry 2013/8305) approved this study and each study participant signed written informed consent in accordance with the Declaration of Helsinki.

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Barceló, C., Sisó, P., de la Rosa, I. et al. M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors. Br J Cancer 127, 1142–1152 (2022). https://doi.org/10.1038/s41416-022-01886-4

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