The integrated stress response and the microenvironment in melanoma progression

黑色素瘤进展中的综合应激反应和微环境

基本信息

批准号：
10391719
负责人：
Colin Goding
金额：
$ 43.03万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391719
关键词：
3-Dimensional Ablation Adipocytes Allografting Anoikis Antioxidants Apoptosis Apoptotic Autophagocytosis BRAF gene Binding Blood Vessels CAV1 gene Cells Coculture Techniques Collagen Complex DNA Sequence Alteration Endothelial Cells Endothelium Equilibrium Experimental Neoplasms Exposure to Extracellular Matrix Fatty Acid Desaturases Fatty Acids Fibroblasts Gene Expression Genes Genetic Genetic Transcription Growth Heterogeneity Human Immunotherapy Impairment Inflammation Integrins Knockout Mice Lead Link Lymph Mediating Mediator of activation protein Melanoma Cell Metastatic Neoplasm to the Lung Modality Modeling Monounsaturated Fatty Acids Mus Neoplasm Metastasis Non-Malignant Nuclear Oncogenes Oncogenic Output Oxygen Pathway interactions Patients Persons Pharmacology Phenotype Primary Neoplasm Publishing Recovery Refractory Reporting Resistance Role Shapes Signal Pathway Signal Transduction Stress Testing Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Tumor-infiltrating immune cells Xenograft procedure angiogenesis biological adaptation to stress endoplasmic reticulum stress gain of function immune checkpoint blockade improved inhibitor melanoma microphthalmia-associated transcription factor mouse model neoplastic cell new therapeutic target novel novel therapeutics nutrient deprivation programs response targeted agent targeted treatment transcription factor tumor tumor growth tumor microenvironment tumorigenic uptake

项目摘要

SUMMARY Despite the emergence novel therapeutic modalities, including BRAF inhibitors and immunotherapies, over 7,100 people are expected to die each year from malignant melanoma, primarily from metastatic dissemination and therapy resistance. The proposed studies leverage the expertise of the two co-PIs in tumor microenvironment, the Integrated Stress Response (ISR) and melanoma progression to test the overall hypothesis that as part of the adaptive response to tumor microenvironmental (TME) stress, bi-directional interactions between melanoma cells and fibroblasts, endothelial cells and adipocytes promote survival, metastatic dissemination, and therapy resistance. Preliminary results and published reports from the two PIs indicate that the ISR is activated in human melanomas and that genetic or pharmacological disruption of the ISR severely impairs primary tumor growth and metastasis in multiple experimental tumors, including melanomas. The studies will delineate the salient roles of the transcription factor ATF4, a major transcriptional effector of the Integrated Stress Response, in a pro-survival and pro-metastatic program mediated by the non- canonical tumor suppressor BRN2, a transcription factor effector of multiple melanoma-associated signaling pathways. To test the central hypothesis, we will pursue three specific aims: In Aim 1 we will use a novel, conditional global ATF4 knockout mouse model, as well as Fibroblast (FB)-specific and Endothelial (EC)- specific ATF4 knockout mice and cells to determine the role of ATF4 expression in each TME component on melanoma progression and metastasis. Preliminary results with global or FB-specific deletion of ATF4 results in a severe deficiency in tumor growth of flank melanoma tumors. In Aim 2 we will study how SRC promotes melanoma progression via ATF4-BRN2 cooperativity. Both BRN2 and ATF4 can repress anoikis/apoptosis, and in preliminary studies we reveal that BRN2 interacts with ATF4. Therefore, we will test the hypothesis that Extracellular Matrix (ECM)-driven integrin signaling, and monounsaturated fatty acid (MUFA) uptake from adipocytes and lymph converge on SRC to impose a cooperative BRN2-ATF4 anti-apoptotic and pro- metastasis gene expression program, driven in part by hippo signaling. Finally, under Aim 3, we will determine how MUFAs dictate melanoma phenotype. Here we will dissect a novel mechanism underpinning MUFA- mediated nuclear localization of -catenin and test the hypothesis that the resulting SRC-driven nuclear CAV1- -catenin complex promotes a pro-metastasis gene expression program via BRN2-ATF4, and the contribution of ATF4 and BRN2 to melanoma phenotypic heterogeneity and tumor immune infiltration. By delineating how the ISR uses ATF4 to coordinate the output of the TME to shape melanoma progression, we will identify therapeutically exploitable pathways for anti-melanoma approaches.

概括尽管出现了新型热模式，包括BRAF抑制剂和免疫疗法，但预计每年有7,100人死于恶性黑色素瘤和耐药性。拟议的研究利用了肿瘤中两个共同核心的专业知识微环境，综合应力反应（ISR）和黑色素瘤进展，以测试总体假设作为对肿瘤微环境（TME）应力的自适应反应的一部分，双向黑色素瘤细胞与成纤维细胞，内皮细胞和脂肪细胞之间的相互作用促进生存，转移性传播和耐药性。初步结果和两个PI的报告表明ISR在人类黑色素瘤中被激活，并且遗传或药物破坏的 ISR严重损害了多种实验肿瘤的原发性肿瘤的生长和转移，包括黑色素瘤。这些研究将描述转录因子ATF4的显着作用，ATF4是主要的转录。综合应力反应的效应因子，在非 - 非生存和促生物的计划中典型的肿瘤抑制剂BRN2，这是多个黑色素瘤相关信号传导的转录因子效应子途径。为了检验中心假设，我们将追求三个特定的目标：在AIM 1中，我们将使用小说，有条件的全局ATF4敲除小鼠模型以及成纤维细胞（FB）特异性和内皮（EC） - 特定的ATF4基因敲除小鼠和细胞确定ATF4表达在每个TME组件上的作用黑色素瘤的进展和转移。 ATF4结果的全局或FB特异性删除的初步结果在AIM 2中，我们将研究SRC如何促进黑色素瘤通过ATF4-BRN2配位进展。 BRN2和ATF4都可以反映Anoikis/凋亡，在初步研究中，我们揭示了BRN2与ATF4相互作用。因此，我们将检验以下假设细胞外基质（ECM）驱动的整联蛋白信号传导和单不饱和脂肪酸（MUFA）的吸收脂肪细胞和淋巴在SRC上收敛，以施加合作的BRN2-ATF4抗凋亡和促进转移基因表达程序，部分由河马信号传导驱动。最后，在AIM 3下，我们将确定 MUFA如何决定黑色素瘤表型。在这里，我们将剖析一种基于mufa-的新型机制 -catenin介导的核定位，并检验了由SRC驱动的核CAV1-的假设 -catenin络合物通过BRN2-ATF4促进了促膜片基因表达程序，并促进了贡献 ATF4和BRN2对黑色素瘤表型异质性和肿瘤免疫浸润的效果。通过描述如何 ISR使用ATF4来协调TME的输出以塑造黑色素瘤的进展，我们将确定用于抗黑道瘤方法的治疗可剥削途径。