The Role of the Integrated Stress Response in Cancer

摘要/总结（总体） 该计划的总体目标是研究综合应激反应（ISR）的作用。 信号通路在肿瘤细胞命运和肿瘤进展中的作用。快速增殖的癌细胞 必须在微环境中茁壮成长，其中代谢营养素如葡萄糖，氧气和 随着肿瘤体积扩大超过已建立的血管分布， 组织。ISR整合来自传感器（如内质网激酶）的信号 PERK和细胞质激酶GCN 2）的细胞营养素的稳态过程，包括 翻译控制、碳和氧代谢以及受体信号传导。ISR还 已被证明有助于癌基因介导的肿瘤进展，这表明它也可能 对由异常癌基因依赖性信号传导引发的生物能量挑战作出反应。的 在拟议的研究中要检验的总体假设是， 在介导MYC依赖性和缺氧依赖性肿瘤中起关键作用 通过其参与和调节参与的关键途径的能力， 昼夜节律、翻译、代谢和免疫功能，从而促进肿瘤细胞 生存和成长。上述假设将通过三个高度综合的项目进行检验： 项目1将定义受ISR控制的miRNA，其功能是微调蛋白质 在ISR/UPR响应期间进行合成。两个关键的microRNA，miR-211和miR-217，是 共同地，它们在内质网应激期间作为Bmal 1的调节剂发挥作用，并且它们对 Bmal 1对淋巴瘤进展的抑制对于肿瘤发生至关重要。项目2将确定 代谢和翻译控制中的关键节点，其由ATF 4 和c-MYC，并描绘共同的转录靶点的共调节机制。它 还将在功能上测试ATF 4在MYC依赖性转化和肿瘤发生中的作用。 项目3将描述ISR诱导的IFNAR 1依赖性和 IFN 1途径的独立失活及其在瘤内细胞活力丧失中的作用 细胞毒性淋巴细胞和免疫特权龛的产生。它也将决定 靶向这些机制是否可以增强抗癌免疫力。这三个项目将 广泛使用核心A（行政）和科学核心B（代谢组学/基因组学） 和C（生物统计学），并已建立了工作，高度合作的关系。 总的来说，我们的三个综合和协同项目将提供一个分子框架， 提出了靶向ISR对抗三种高度恶性肿瘤的潜在功效， 常见和致命的肿瘤

ABSTRACT/SUMMARY (Overall) The overall goal of this Program is to investigate the role of the Integrated Stress Response (ISR) signaling pathway in tumor cell fate and tumor progression. Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. The ISR integrates signals from sensors (such as the endoplasmic reticulum kinase PERK and cytoplasmic kinase GCN2) of cellular nutrients to homeostatic processes including translational control, carbon and oxygen metabolism and receptor signaling. The ISR has also been shown to facilitate oncogene-mediated tumor progression, suggesting that it may also respond to bioenergetic challenges triggered by aberrant oncogene-dependent signaling. The overall hypothesis to be tested in the proposed studies is that the Integrated Stress Response plays a pivotal role in mediating MYC-dependent and hypoxia-dependent tumor progression through its capacity to engage and regulate key pathways involved in circadian, translational, metabolic and immune functions thereby facilitating tumor cell survival and growth. The above hypothesis will be tested by three highly integrated projects: Project 1 will define miRNAs subject to ISR control whose function is to fine-tune protein synthesis during an ISR/UPR response. Two key, microRNAs, miR-211 and miR-217, are the focus; collectively, they function as regulators of Bmal1 during ER stress and their contribution to Bmal1 repression to lymphoma progression is critical for tumorigenesis. Project 2 will identify critical nodes in metabolism and translation control which are coordinately regulated by both ATF4 and c-MYC and delineate the mechanism of co-regulation of common transcriptional targets. It will also functionally test the role of ATF4 in MYC-dependent transformation and tumorigenesis. Project 3 will delineate the mechanisms underlying ISR-induced IFNAR1-dependent and independent inactivation of the IFN1 pathway, its role in the loss of viability of intratumoral cytotoxic lymphocytes and the generation of the immune privileged niches. It will also determine whether targeting these mechanisms can augment anti-cancer immunity. All three projects will make extensive use of Core A (Administrative) and scientific Cores B (Metabolomics/Genomics) and C (Biostatistics) and have already established a working, highly collaborative relationship. Collectively, our three integrated and synergistic Projects will provide a molecular framework that addresses the potential efficacy of targeting the ISR to antagonize malignancy in three highly prevalent and lethal types of tumors.