Control of cytokine responses through the MITF-IRF4 transcription factor network in melanoma

• Applicant: Professor Dr. Michael Hölzel
• Subject Area: Dermatology ; Hematology, Oncology
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251103840

Malignant melanoma is an aggressive skin cancer that originates from pigment producing melanocytes. Ultraviolet light (UV) irradiation is a major risk factor that causes oncogenic genomic aberrations. Besides melanoma cell intrinsic alterations, primary melanomas frequently have immune cell infiltrates indicating an important role of the tumor microenvironment and cytokine responses in the development and progression of the disease. Sustained inflammation following ultraviolet light (UV) irradiation has been linked to melanomagenesis through the unexpected involvement of an interferon-gamma driven cytokine loop between melanocytes and macrophages. We hypothesized that some genetic predispositions linked to increased melanoma risk and altered pigmentation traits might also affect cytokine crosstalk. We devised an integrative bioinformatic discovery approach and identified the melanoma susceptibility gene IRF4 (interferon-regulatory factor 4) as potential determinant of cytokine responses in melanocytes and melanoma cells. So far, IRF4 is considered as a lymphoid restricted transcription factor that orchestrates cytokine responses and acts as lineage oncogene in certain B cell malignancies, but its contribution to normal melanocyte and melanoma cell function is currently unknown. We found high expression of IRF4 in melanomas and a role in melanoma cell differentiation and interferon responses. In this first part of the project we will scrutinize how the melanoma susceptibility gene IRF4 controls melanocytic differentiation and cytokine responses and explore its role as potential determinant for immunotherapies.Melanocytes also communicate with keratinocytes and fibroblasts through a specialized repertoire of receptors and signaling molecules provided by the melanocytic lineage transcription factor MITF-M (microphthalmia-associated transcription factor). In the course of melanoma progression MITF-M becomes heterogeneously expressed and this likely imposes a strong context dependency of cytokine and growth factor signaling due to variable MITF-M dependent receptor expression. Based on literature we hypothesize that one clinically relevant example is the HGF (hepatocyte growth factor) signaling cascade. Recently, HGF received a lot of attention because high levels of HGF predicted poor responders among melanoma patients treated with BRAF inhibitors. A mutated and activated form of the BRAF kinase is found in about the half of all melanomas and some BRAF mutated melanomas strongly respond to BRAF blockade whereas others do not. In this second part of the project we aim to scrutinize the context-dependency the HGF signaling cascade, as this is critical for our further understanding of the role of HGF in BRAF inhibitor resistance, in particular with respect to phenotypic heterogeneity, and the delineation of advanced therapeutic strategies.

• DFG Programme: Research Grants