title: IGF-1 contributes to the expansion of melanoma-initiating cells through an epithelial-mesenchymal transition process.
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.
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Le Coz
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Chaobin
authors.initials: C
authors.lastname: Zhu
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Devocelle
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Aimé
authors.initials: A
authors.lastname: Vazquez
authors.affiliation: INSERM UMRS 1193, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Boucheix
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Azzi
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Gallerne
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Lecourt
authors.affiliation: INSERM UMRS 1197, Hôpital Paul Brousse, 94807 Villejuif Cedex, France.|Université Paris-Saclay 91190, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Giron-Michel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008810:Mice, Inbred C57BL; D008942:Mitoxantrone / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D008942:Mitoxantrone
keywords: EMT; IGF-1; chemoresistance; melanoma-initiating cells; metastasis