ER Stress and Mitochondrial Biogenesis in Melanoma

描述(由申请人提供)：我们最近见证了我们对黑色素瘤的理解和抗黑色素瘤疗法的发展方面的重大进步。抗BRAF治疗的有限成功促进了基因组途径和最近的非基因组途径的激增，使BRAF阻断和转移表型得以绕过。代谢改变和细胞内质网应激反应位于黑色素瘤耐药和转移表型的结合点，也是我们应用的重点，它将主要调节因子-MITF、PGC1与UPR传感机制联系在一起。具体地说，我们的竞争更新侧重于黑色素瘤临床管理中最关键的两个障碍--其侵袭性(转移倾向)和获得耐药性。这些表型变化是黑色素瘤倾向于适应恶劣的微环境条件的结果，包括营养物质的缺乏、氧气紧张和各种药物的治疗。因此，我们假设代谢调节和未折叠蛋白反应的协调变化影响MITF，并且是黑色素瘤耐药和侵袭性表型的基础。我们的初步结果表明，黑色素瘤的重新编程涉及MITF、PGC1和ATF4/Siah1之间的新联系。我们的三个项目和两个科学核心预计将开发新的范式，使人们能够更好地了解黑色素瘤的可塑性--它是重新编程的基础--并提供治疗侵袭性和耐药性疾病的创新治疗方法。我们组建了一支在黑色素瘤(Goding、Ronai和Bosenberg)、新陈代谢(Smith和Kelly)和未折叠蛋白质反应(Kaufman)领域拥有国际知名专业知识的团队。这些研究人员将与我们的代谢组学(Osterman)和多重药物筛选(Stern)核心的专家领导合作。我们将(I)确定UPR组分(Siah1异构体2、ATF4、CHOP)在黑色素瘤转移和治疗耐药中的作用(Ii)确定增殖物激活受体γ共激活物(PGC-1α/β)及其下游信号在黑色素瘤发生和耐药中的作用；(Iii)了解MITF和ATF4之间的反馈环以及由此产生的下游代谢变化在获得侵袭性和耐药表型中的作用和调节。所有三个项目都将依赖于允许新陈代谢组学评估的核心的支持(核心B)、在相关的人类黑色素瘤和遗传模型中的验证以及合成致死筛选(核心C)和协调管理(核心A)。最终，我们的工作有望确定新的治疗策略，以克服黑色素瘤的耐药性和转移疾病。

DESCRIPTION (provided by applicant): We recently witnessed major advances in both our understanding of melanoma and in the development of antimelanoma therapeutics. The limited success of anti-BRAF therapy fuelled a surge in genomic and more recently non-genomic pathways that enabled the bypass of BRAF-blockade as well as metastatic phenotype. Altered metabolism and cellular ER stress response are positioned at the nexus of melanoma resistance and metastatic phenotypes, and are the focus on our application, which interlinks the master regulators-MITF, PGC1 with the UPR sensing machinery. Specifically, our competitive renewal focuses on two of the most critical obstacles in the clinical management of melanoma-its invasiveness (propensity to metastasize) and the acquisition of drug resistance. These phenotypic changes are a result of the propensity of melanoma to adapt to harsh microenvironmental conditions including the deprivation of nutrients, oxygen tension, and treatment with various drugs. Accordingly, we hypothesize that coordinated changes in metabolic regulation and the unfolded protein response affects MITF and underlies drug-resistant and invasive phenotype in melanoma. Our preliminary results suggest that melanoma reprogramming involves novel connection between the MITF, PGC1, and ATF4/Siah1. Our three projects and two scientific cores are expected to develop new paradigms enabling a better understanding of melanoma plasticity-the underpinning of its reprogramming-and offer innovative therapeutic approaches to treat invasive and drug resistant disease. We have assembled a team with internationally renowned expertise in the field of melanoma (Goding, Ronai, and Bosenberg), metabolism (Smith and Kelly), and the unfolded protein response (Kaufman). These investigators will collaborate with expert leaders of our Metabolomics (Osterman) and Multiplex Drug Screening (Stern) Cores. Together we will (I): Define the role of UPR components (Siah1 isoform 2, ATF4, CHOP) in melanoma metastasis and resistance to therapy (II) Determine the role of proliferator-activated receptor γ coactivators (PGC-1α/β) and downstream signaling in melanoma and acquisition of drug resistance and (III) understand the role and regulation of a feedback loop between MITF and ATF4, and the resulting downstream metabolic alterations, in acquisition of the invasive and drug-resistant phenotype of melanoma. All three projects will rely on the support by cores allowing metabolomics assessment (Core B), validation in relevant human melanoma tumors and genetic models as well as synthetic lethal screen (Core C) and coordinated administration (Core A). Ultimately, our work is expected to identify new therapeutic strategies for overcoming drug resistance and metastatic disease in melanoma.