IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process

// Vincent Le Coz 1, 3, * , Chaobin Zhu 1, 3, * , Aurore Devocelle 1, 3 , Aime Vazquez 1, 3 , Claude Boucheix 2, 3 , Sandy Azzi 1, 3 , Cindy Gallerne 1, 3 , Pierre Eid 1, 3 , Severine Lecourt 1, 3, * , Julien Giron-Michel 1, 3, * 1 INSERM UMRS 1197, Hopital Paul Brousse, 94807 Villejuif Cedex, France 2 INSERM UMRS 1193, Hopital Paul Brousse, 94807 Villejuif Cedex, France 3 Universite Paris-Saclay, 91190, France * These authors contributed equally to this work Correspondence to: Julien Giron-Michel, email: julien.giron-michel@inserm.fr Keywords: IGF-1, melanoma-initiating cells, metastasis, EMT, chemoresistance Received: July 13, 2016      Accepted: October 12, 2016      Published: October 18, 2016 ABSTRACT Melanoma is a particularly virulent human cancer, due to its resistance to conventional treatments and high frequency of metastasis. Melanomas contain a fraction of cells, the melanoma-initiating cells (MICs), responsible for tumor propagation and relapse. Identification of the molecular pathways supporting MICs is, therefore, vital for the development of targeted treatments. One factor produced by melanoma cells and their microenvironment, insulin-like growth factor-1 (IGF- 1), is linked to epithelial-mesenchymal transition (EMT) and stemness features in several cancers. We evaluated the effect of IGF-1 on the phenotype and chemoresistance of B16-F10 cells. IGF-1 inhibition in these cells prevented malignant cell proliferation, migration and invasion, and lung colony formation in immunodeficient mice. IGF-1 downregulation also markedly inhibited EMT, with low levels of ZEB1 and mesenchymal markers (N-cadherin, CD44, CD29, CD105) associated with high levels of E-cadherin and MITF, the major regulator of melanocyte differentiation. IGF-1 inhibition greatly reduced stemness features, including the expression of key stem markers (SOX2, Oct-3/4, CD24 and CD133), and the functional characteristics of MICs (melanosphere formation, aldehyde dehydrogenase activity, side population). These features were associated with a high degree of sensitivity to mitoxantrone treatment. In this study, we deciphered new connections between IGF-1 and stemness features and identified IGF-1 as instrumental for maintaining the MIC phenotype. The IGF1/IGF1-R nexus could be targeted for the development of more efficient anti-melanoma treatments. Blocking the IGF-1 pathway would improve the immune response, decrease the metastatic potential of tumor cells and sensitize melanoma cells to conventional treatments.