Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance

黑色素瘤转移和耐药性之间的信号重新连接

• 批准号: 8955610
• 负责人: Ze'ev A Ronai
• 金额: $ 116.3万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-02 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955610
• 关键词: ATF2 gene; Autophagocytosis; BRAF gene; Breast Cancer Patient; Cell Death; Cellular Stress Response; Complement; Development; Drug resistance; Epigenetic Process; Exhibits; Future; Gap Junctions; Gene Expression; Genetic; Glutamine; Hypoxia; Hypoxia Pathway; Immunologic Surveillance; Investigation; Lesion; MAPK8 gene; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metabolism; Methods; Modality; Monitor; Mutate; Mutation; Neoplasm Metastasis; Nutrient; Oncogenic; PDPK1 gene; Phenotype; Phosphotransferases; Play; RNA Splicing; Resistance; Role; Signal Transduction; Stress; Stress Response Signaling; Tumor Suppressor Proteins; base; biological adaptation to stress; cancer cell; endoplasmic reticulum stress; gain of function; inhibitor/antagonist; melanoma; neoplastic cell; novel; novel therapeutics; prevent; programs; public health relevance; response; therapy resistant; transcription factor; tumor; ubiquitin ligase

 DESCRIPTION (provided by applicant): Malignant cells are continuously exposed to extrinsic (hypoxia, limited access to nutrients, immune surveillance) and intrinsic (oncogenic insults) stresses that culminate in activation of the hypoxia and endoplasmic reticulum stress (ERS) response programs. Tumor cell adaptation to these challenges depends on both genetic (acquisition of new mutations) and epigenetic (modulation of gene expression) mechanisms that underlie tumor survival, metastasis, and resistance to therapy; also known as plasticity. Over the past two decades, my lab has focused on understanding the cellular stress response, particularly the contribution of kinases and ubiquitin ligases. Our studies established a number of paradigms in stress adaptation, with demonstrated significance for the development, progression, and drug resistance of both melanoma and prostate cancer. We defined how subcellular localization dictates the oncogenic or tumor suppressor activity of ATF2, and showed that this is regulated by the AGC kinase PKC. Based on this discovery we performed a screen for inhibitors of this transcription factor-ostensibly undruggable targets- based on altered subcellular localization. Our other recent discovery of a spliced form of ATF2 that exhibits a gain-of-function phenotype will enable us to further redefine the function of ATF2 in melanoma. Further, we identified a mechanism of rewired signaling in which ERK impacts JNK with concomitant effects on PDK1, the master regulator of AGC kinases. This led us to demonstrate the key role played by PDK1 in melanoma. Our future studies will continue to investigate how PDK1 and its downstream targets contribute to melanoma metastasis and drug resistance. Our discovery that the ubiquitin ligases Siah1/2 control the hypoxia response revealed their roles in melanoma and the most aggressive forms of prostate cancer. Siah1/2 also control stress response signaling, establishing a mechanism for commitment to cell death under ischemic conditions. This established the basis upon which we will develop and evaluate first-in-class Siah inhibitors for prostate cancer and melanoma metastasis and resistance. We also recently determined that the RNF5 ubiquitin ligase regulates both autophagy and glutamine metabolism and established a new method to stratify breast cancer patients to select therapies. Lastly, the discovery that RNF125 ubiquitin ligase is a key regulator of melanoma resistance to BRAF inhibitors will drive an investigation in pancreatic cancer, a fraction of which carry mutated RNF125. Collectively, our discoveries reveal that the tumor cell response to stress, which underlies their plasticity, involves the cooperation between rewired signaling and genetic lesions. Our proposed studies will establish novel mechanisms underlying tumor plasticity, enabling the development of novel agents for predicting, monitoring, and preventing tumor metastasis and resistance.

 描述（由申请方提供）：恶性细胞持续暴露于外源性（缺氧、营养物质获取受限、免疫监视）和内源性（致癌损伤）应激，最终激活缺氧和内质网应激（ERS）反应程序。肿瘤细胞对这些挑战的适应取决于遗传（获得新突变）和表观遗传（基因表达的调节）机制，这些机制是肿瘤生存、转移和对治疗的抗性的基础;也称为可塑性。在过去的二十年里，我的实验室一直专注于了解细胞的应激反应，特别是激酶和泛素连接酶的贡献。我们的研究建立了一些应激适应的范例，证明了黑色素瘤和前列腺癌的发展，进展和耐药性的重要性。我们确定了亚细胞定位如何决定ATF 2的致癌或抑癌活性，并表明这是由AGC激酶PKC β调节的。基于这一发现，我们进行了一个屏幕上的抑制剂，这种转录因子-表面上undruggable目标-基于改变亚细胞定位。我们最近发现的另一种剪接形式的ATF 2表现出功能获得性表型，这将使我们能够进一步重新定义ATF 2在黑色素瘤中的功能。此外，我们确定了一种重新连接信号的机制，其中ERK影响JNK，同时影响AGC激酶的主要调节因子PDK 1。这使我们证明了PDK 1在黑色素瘤中发挥的关键作用。我们未来的研究将继续研究PDK 1及其下游靶点如何促进黑色素瘤转移和耐药性。我们发现泛素连接酶Siah 1/2控制缺氧反应，揭示了它们在黑色素瘤和最具侵袭性的前列腺癌中的作用。Siah 1/2还控制应激反应信号，建立了在缺血条件下细胞死亡的机制。这为我们开发和评估前列腺癌和黑色素瘤转移和耐药性的一流Siah抑制剂奠定了基础。我们最近还确定了RNF 5泛素连接酶调节自噬和谷氨酰胺代谢，并建立了一种新的方法来分层乳腺癌患者选择治疗。最后，RNF 125泛素连接酶是黑色素瘤对BRAF抑制剂耐药性的关键调节因子，这一发现将推动对胰腺癌的研究，其中一部分携带突变的BRAF抑制剂。 RNF125。总的来说，我们的发现揭示了肿瘤细胞对压力的反应，这是它们可塑性的基础，涉及重新连接的信号和遗传病变之间的合作。我们提出的研究将建立肿瘤可塑性的新机制，从而能够开发用于预测、监测和预防肿瘤转移和耐药的新药物。