Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice.
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/Ar...
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2012
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oai:doaj.org-article:d167be50080642eabd99670a5d3de3252021-11-18T08:08:21ZEpithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice.1932-620310.1371/journal.pone.0049419https://doaj.org/article/d167be50080642eabd99670a5d3de3252012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23173060/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203We 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.Maria WehbeSaïdi M SoudjaAmandine MasLionel ChassonRodolphe GuinamardCéline Powis de TenbosscheGrégory VerdeilBenoît Van den EyndeAnne-Marie Schmitt-VerhulstPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e49419 (2012) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Maria Wehbe Saïdi M Soudja Amandine Mas Lionel Chasson Rodolphe Guinamard Céline Powis de Tenbossche Grégory Verdeil Benoît Van den Eynde Anne-Marie Schmitt-Verhulst Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| description |
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. |
| format |
article |
| author |
Maria Wehbe Saïdi M Soudja Amandine Mas Lionel Chasson Rodolphe Guinamard Céline Powis de Tenbossche Grégory Verdeil Benoît Van den Eynde Anne-Marie Schmitt-Verhulst |
| author_facet |
Maria Wehbe Saïdi M Soudja Amandine Mas Lionel Chasson Rodolphe Guinamard Céline Powis de Tenbossche Grégory Verdeil Benoît Van den Eynde Anne-Marie Schmitt-Verhulst |
| author_sort |
Maria Wehbe |
| title |
Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| title_short |
Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| title_full |
Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| title_fullStr |
Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| title_full_unstemmed |
Epithelial-mesenchymal-transition-like and TGFβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| title_sort |
epithelial-mesenchymal-transition-like and tgfβ pathways associated with autochthonous inflammatory melanoma development in mice. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/d167be50080642eabd99670a5d3de325 |
| work_keys_str_mv |
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