Epithelial-Mesenchymal-Transition-Like and TGFβ Pathways Associated with Autochthonous Inflammatory Melanoma Development in Mice

• DOI: 10.1371/journal.pone.0049419
• Publication Date: 2012-11-16T22:11:00Z
• Authors: Maria Wehbe; Saïdi M. Soudja; Amandine Mas; Lionel Chasson; Rodolphe Guinamard; Céline Powis de T...; Grégory Verdeil; Benoît Van den Eynde; Anne-Marie Schmit...
• Keywords: Microphthalmia-associated transcription factor; Proinflammatory cytokine

We compared gene expression signatures of aggressive amelanotic (Amela) melanomas with those slowly growing pigmented (Mela), identifying pathways potentially responsible for the Amela phenotype. Both tumors develop in mice upon conditional deletion melanocytes Ink4a/Arf tumor suppressor genes concomitant oncogene H-RasG12V and a known antigen. previously showed that only were highly infiltrated by leukocytes local systemic inflammation. report present pattern de-differentiation reduced involved pigmentation. This correlates enhanced expression, respectively, microphthalmia-associated (Mitf) Pou3f2/Brn-2 transcription factors. The Mitf-controlled melanocyte differentiation antigens also observed some human cutaneous melanoma has important implications immunotherapy protocols generally target such antigens. Induced express Epithelial-Mesenchymal-Transition (EMT)-like TGFβ-pathway signatures. These are correlated constitutive Smad3 signaling cell lines. Signatures infiltrating chemokines as chemotactic cytokine ligand 2 (Ccl2) contribute to leukocyte recruitment further characterize tumors. Inhibition mitogen-activated protein kinase (MAPK) activation pathway lines leads EMT hallmark inhibits both proinflammatory Ccl2 production cells. results indicate link between EMT-like processes alterations immune functions, being controlled MAPK pathway. They suggest targeting within cells will impact tumor-intrinsic oncogenic properties well nature microenvironment.