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

基本信息

批准号：
9213360
负责人：
Ze'ev A Ronai
金额：
$ 113.75万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
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/9213360
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

项目摘要

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（由申请人提供）：恶性肿瘤细胞持续暴露于外在（缺氧、营养物质获取受限、免疫监视）和内在（致癌损伤）应激下，最终导致缺氧和内质网应激（ERS）肿瘤反应程序的激活。细胞对这些挑战的适应取决于肿瘤生存、转移和耐药性的遗传（获得新突变）和表观遗传（基因表达的调节）机制在过去的二十年里，我的实验室一直致力于了解细胞应激反应，特别是激酶和泛素连接酶的贡献，我们的研究建立了许多应激适应的范例，这对应激适应具有重要意义。我们定义了亚细胞定位如何决定 ATF2 的致癌或肿瘤抑制活性，并表明这是由 AGC 激酶 PKC 调节的。基于这一发现，我们基于改变的亚细胞定位对这种表面上不可成药的靶标的抑制剂进行了筛选。我们最近发现的 ATF2 剪接形式表现出功能获得表型，这将使我们能够进一步重新定义。此外，我们还发现了一种信号重新连接机制，其中 ERK 影响 JNK，同时对 AGC 激酶的主要调节因子 PDK1 产生影响。我们未来的研究将继续研究 PDK1 及其下游靶标如何促进黑色素瘤转移和耐药性。我们发现泛素连接酶 Siah1/2 控制缺氧反应，揭示了它们在黑色素瘤和耐药性中的作用。 Siah1/2 最具侵袭性的前列腺癌也控制应激反应信号，建立了缺血条件下细胞死亡的机制，这为我们开发和评估奠定了基础。我们最近还确定 RNF5 泛素连接酶可调节自噬和谷氨酰胺代谢，并建立了一种对乳腺癌患者进行分层以选择治疗方法的新方法。 RNF125 泛素连接酶是黑色素瘤对 BRAF 抑制剂耐药的关键调节因子，将推动对胰腺癌的研究，其中一部分携带突变 RNF125。总的来说，我们的发现揭示了肿瘤细胞对压力的反应，这是其可塑性的基础，涉及重新连接的信号传导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，从而能够开发出用于预测的新药物。监测，预防肿瘤转移和耐药。