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

通过 MITF-IRF4 转录因子网络控制黑色素瘤中的细胞因子反应

• 批准号: 251103840
• 负责人: Professor Dr. Michael Hölzel
• 金额: --
• 依托单位: Institut für Experimentelle Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/251103840?language=en
• 关键词: Control; cytokine; responses; through; MITF

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.

恶性黑色素瘤是一种侵袭性的皮肤癌，源自产生黑色素细胞的色素。紫外线（UV）辐射是导致致癌基因组畸变的主要危险因素。除了黑色素瘤细胞的固有改变外，原发性黑色素瘤经常具有免疫细胞浸润，表明肿瘤微环境和细胞因子反应在疾病的发育和进展中起重要作用。紫外线（UV）辐射后持续的炎症与黑色素促性细胞和巨噬细胞之间的干扰素驱动的细胞因子环的意外参与，与黑色素作用有关。我们假设某些与黑色素瘤风险增加和色素沉着性状有关的遗传易感性也可能影响细胞因子串扰。我们设计了一种综合生物信息学发现方法，并确定了黑色素瘤易感性基因IRF4（干扰素调节因子4）为黑色素细胞和黑色素瘤细胞中细胞因子反应的潜在决定因素。到目前为止，IRF4被认为是淋巴限制的转录因子，它在某些B细胞恶性肿瘤中策划了细胞因子反应并充当谱系癌，但目前尚不清楚其对正常黑色素细胞和黑色素瘤细胞功能的贡献。我们发现IRF4在黑色素瘤中的高表达以及在黑色素瘤细胞分化和干扰素反应中的作用。在项目的第一部分中，我们将仔细检查黑色素瘤易感性基因IRF4如何控制黑素细胞分化和细胞因子反应，并探索其作为免疫疗法的潜在决定因素的作用。麦芽素细胞还通过角质细胞和成纤维细胞通过专门的融合量和信号来沟通。 MITF-M（与摩托治疗相关的转录因子）。在黑色素瘤进展的过程中，MITF-M的表达形式表达，这很可能施加了由于MITF-M依赖性受体表达而引起的细胞因子和生长因子信号的强烈依赖性。根据文献，我们假设一个临床相关的例子是HGF（肝细胞生长因子）信号传导级联。最近，HGF受到了很多关注，因为高水平的HGF预测接受BRAF抑制剂治疗的黑色素瘤患者的反应者差。在所有黑色素瘤的大约一半中发现了BRAF激酶的突变形式，一些BRAF突变的黑色素瘤对BRAF封锁强烈反应，而其他BRAF则没有。在项目的第二部分中，我们旨在审查上下文依赖性HGF信号级联，因为这对于我们进一步理解HGF在BRAF抑制剂耐药性中的作用至关重要，特别是在表型异质性方面，以及对先进治疗策略的描述。