title: Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice.
abstract: We compared gene expression signatures of aggressive amelanotic (Amela) melanomas with those of slowly growing pigmented melanomas (Mela), identifying pathways potentially responsible for the aggressive Amela phenotype. Both tumors develop in mice upon conditional deletion in melanocytes of Ink4a/Arf tumor suppressor genes with concomitant expression of oncogene H-Ras(G12V) and a known tumor antigen. We previously showed that only the aggressive Amela tumors were highly infiltrated by leukocytes concomitant with local and systemic inflammation. We report that Amela tumors present a pattern of de-differentiation with reduced expression of genes involved in pigmentation. This correlates with reduced and enhanced expression, respectively, of microphthalmia-associated (Mitf) and Pou3f2/Brn-2 transcription factors. The reduced expression of Mitf-controlled melanocyte differentiation antigens also observed in some human cutaneous melanoma has important implications for immunotherapy protocols that generally target such antigens. Induced Amela tumors also express Epithelial-Mesenchymal-Transition (EMT)-like and TGFβ-pathway signatures. These are correlated with constitutive Smad3 signaling in Amela tumors and melanoma cell lines. Signatures of infiltrating leukocytes and some chemokines such as chemotactic cytokine ligand 2 (Ccl2) that contribute to leukocyte recruitment further characterize Amela tumors. Inhibition of the mitogen-activated protein kinase (MAPK) activation pathway in Amela tumor lines leads to reduced expression of EMT hallmark genes and inhibits both proinflammatory cytokine Ccl2 gene expression and Ccl2 production by the melanoma cells. These results indicate a link between EMT-like processes and alterations of immune functions, both being controlled by the MAPK pathway. They further suggest that targeting the MAPK pathway within tumor cells will impact tumor-intrinsic oncogenic properties as well as the nature of the tumor microenvironment.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy-CIML, Aix-Marseille Université UM2, Marseille, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Wehbe
authors.forename: Saïdi M
authors.initials: SM
authors.lastname: Soudja
authors.forename: Amandine
authors.initials: A
authors.lastname: Mas
authors.forename: Lionel
authors.initials: L
authors.lastname: Chasson
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Guinamard
authors.forename: Céline Powis
authors.initials: CP
authors.lastname: de Tenbossche
authors.forename: Grégory
authors.initials: G
authors.lastname: Verdeil
authors.forename: Benoît
authors.initials: B
authors.lastname: Van den Eynde
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D018328:Melanoma, Amelanotic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D050809:POU Domain Factors / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018932:Chemokine CCL2; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C074066:Pou3f2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases