title: Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells.
abstract: Despite progress in the understanding of the biology and genetics of melanoma, no effective treatment against this cancer is available. The adjacent microenvironment has an important role in melanoma progression. Defining the molecular signals that control the bidirectional dialog between malignant cells and the surrounding stroma is crucial for efficient targeted therapy. Our study aimed at defining the role of sphingosine-1-phosphate (S1P) in melanoma-stroma interactions. Transcriptomic analysis of human melanoma cell lines showed increased expression of sphingosine kinase-1 (SPHK1), the enzyme that produces S1P, as compared with normal melanocytes. Such an increase was also observed by immunohistochemistry in melanoma specimens as compared with nevi, and occurred downstream of ERK activation because of BRAF or NRAS mutations. Importantly, migration of melanoma cells was not affected by changes in SPHK1 activity in tumor cells, but was stimulated by comparable modifications of S1P-metabolizing enzymes in cocultured dermal fibroblasts. Reciprocally, incubation of fibroblasts with the conditioned medium from SPHK1-expressing melanoma cells resulted in their differentiation to myofibroblasts, increased production of matrix metalloproteinases and enhanced SPHK1 expression and activity. In vivo tumorigenesis experiments showed that the lack of S1P in the microenvironment prevented the development of orthotopically injected melanoma cells. Finally, local tumor growth and dissemination were enhanced more efficiently by coinjection of wild-type skin fibroblasts than by fibroblasts from Sphk1(-/-) mice. This report is the first to document that SPHK1/S1P modulates the communication between melanoma cells and dermal fibroblasts. Altogether, our findings highlight SPHK1 as a potential therapeutic target in melanoma progression.
authors.affiliation: 1] Inserm UMR1037, Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France [2] Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: V
authors.initials: V
authors.lastname: Albinet
authors.affiliation: 1] Inserm UMR1037, Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France [2] Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: M-L
authors.initials: ML
authors.lastname: Bats
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Huwiler
authors.affiliation: Service d'anatomie et cytologie pathologiques, Toulouse, France.
authors.forename: P
authors.initials: P
authors.lastname: Rochaix
authors.affiliation: Département d'oncologie médicale, Institut Claudius Regaud, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Chevreau
authors.affiliation: 1] Inserm UMR1037, Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France [2] Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Ségui
authors.affiliation: 1] Inserm UMR1037, Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France [2] Université Toulouse III Paul-Sabatier, Toulouse, France [3] Laboratoire de Biochimie Métabolique, CHU, Toulouse, France.
authors.forename: T
authors.initials: T
authors.lastname: Levade
authors.affiliation: 1] Inserm UMR1037, Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France [2] Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: N
authors.initials: N
authors.lastname: Andrieu-Abadie
mesh_terms: D000446:Aldehyde-Lyases / Q000235:genetics; D000818:Animals; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology*; D020558:GTP Phosphohydrolases / Q000235:genetics; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000201:enzymology / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000201:enzymology / Q000473:pathology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000446:Aldehyde-Lyases; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; D008246:Lysophospholipids; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008565:Membrane Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D048493:Proto-Oncogene Proteins B-raf; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C482119:BRAF protein, human; C522361:MMP2 protein, human; C579270:MMP9 protein, human; C579846:NRAS protein, human; C022649:sphingosine 1-phosphate lyase (aldolase)