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Role of AMPK in melanoma brain metastasis

AMPK 在黑色素瘤脑转移中的作用

基本信息

批准号：
10927688
负责人：
Vashisht G Yennu Nanda
金额：
$ 18.82万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10927688
关键词：
5&apos -AMP-activated protein kinase ATP Citrate (pro-S)-Lyase Address Anchorage-Independent Growth BRAF gene Biguanides Biology Brain Catalytic Domain Cell model Cephalic Cessation of life Clinical Complex Computational Biology Cutaneous Melanoma Diabetes Mellitus Disease Disseminated Malignant Neoplasm Drug Targeting Enzymes Genes Genetically Engineered Mouse Growth Homeostasis Human Immune Immunotherapy Knock-out Knowledge MEKs Malignant Neoplasms Melanoma Cell Memorial Sloan-Kettering Cancer Center Metabolic Metabolism Metastatic Melanoma Metastatic malignant neoplasm to brain Metformin Mitochondria Modeling Monitor Mus Mutate Mutation NF1 gene NF1 mutation Neoplasm Metastasis Nude Mice Oncologist Oxidative Phosphorylation Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phenformin Phosphorylation Inhibition Proliferating Regulation Reporting Research Personnel Role Sampling Signal Pathway Signal Transduction Soft Agar Assay Solid Neoplasm Surgeon The Cancer Genome Atlas Therapeutic Therapeutic Effect Tumor Promotion University of Texas M D Anderson Cancer Center Xenograft Model Xenograft procedure cancer cell cancer genomics cancer survival cellular targeting cost estimate genomic data immune checkpoint blockade inhibitor insight lipid biosynthesis melanoma metabolomics mouse model mutant new therapeutic target novel novel therapeutic intervention phase 1 study pre-clinical response sensor single-cell RNA sequencing subcutaneous targeted treatment therapeutically effective tumor tumor metabolism tumor progression tumor xenograft years of life lost

项目摘要

Project Summary: AMP activated protein kinase (AMPK) is a critical evolutionarily conserved energy sensor that regulates energy homeostasis by monitoring changes in the intracellular AMP or ADP to ATP ratios. Mounting evidence supports that the AMPK pathway is one of the major signaling players at the interface of metabolism and cancer. However, the role of AMPK in tumor progression and metastasis remains obscure. Our recent analysis on melanoma cancer genomics data has revealed that the mutations in the PRKAA2 gene, which encodes the alpha 2 catalytic subunit of AMPK, occur in 8-10% of cutaneous melanomas and tend to co-occur with NF1 mutations. In our preliminary studies, we found that knockout of AMPKα2 promoted anchorage-independent growth of mutant NF1-melanoma cells in soft agar assays and their growth as xenografted tumors in nude mice. Importantly, we found that expression of AMPKα2 is significantly downregulated in human melanoma brain metastasis samples compared to patient-matched extracranial metastasis samples. Furthermore, knockout of AMPKα2 promoted brain metastasis of NF1-mutant Mewo melanoma cells in nude mice. Based on these preliminary results, we hypothesize that inactivation of AMPKα2 in melanoma promotes tumor progression to melanoma brain metastasis. In Aim 1, we will establish the role of AMPKα2 in melanoma brain metastasis using mouse models and human samples. We plan to characterize the effects of AMPKα2 loss in both syngeneic and genetically engineered mouse models. Human melanoma brain metastasis samples will be used to explore the contribution of AMPKα2 loss through spatial single cell RNA-seq analyses. In aim 2, we will characterize downstream targets of AMPK involved in the metabolic regulation of melanoma brain metastasis. We will investigate the contribution of a novel putative substrate of AMPKα2 involved in de novo lipogenesis, identified in our preliminary studies, to melanoma brain metastasis, and explore additional new AMPKα2 targets through comprehensive metabolomics and RPPA analyses of tumor samples from mouse models. In aim 3, we will assess the therapeutic effects of metabolic drugs targeting the AMPK pathway on enhancing the efficacies of targeted- and immune- therapies in melanoma brain metastasis using human melanoma xenografts, syngeneic and genetically engineered mouse models. To achieve these aims, we have assembled a team of investigators with various expertise including cancer cell metabolism, melanoma brain metastasis biology, melanoma oncologists/surgeon and computational biology. Our study will not only provide critical insights into the role of AMPK metabolic signaling in melanoma brain metastasis addressing a significant knowledge gap in the field, but also identify novel therapeutic approaches to target melanoma brain metastasis.

项目总结： AMP激活的蛋白激酶(AMPK)是一种关键的进化保守的能量感受器，调节通过监测细胞内AMP或ADP/ATP比率的变化来实现能量动态平衡。越来越多的证据支持AMPK通路是新陈代谢与癌症交界处的主要信号传递者之一。然而，AMPK在肿瘤进展和转移中的作用仍然不清楚。我们最近对黑色素瘤癌症基因组学数据显示，编码阿尔法的PRKAA2基因的突变 2 AMPK催化亚单位，出现在8-10%的皮肤黑色素瘤中，并倾向于与NF1突变共存。在我们的初步研究中，我们发现敲除AMPKα2促进了锚定非依赖性的生长软琼脂实验中突变的nf1黑色素瘤细胞及其作为裸鼠移植瘤的生长。重要的是，我们发现AMPKα2在人黑色素瘤脑中的表达显著下调将转移样本与患者匹配的颅外转移样本进行比较。此外，基因敲除 AMPKNF1-α-2促进裸鼠突变型Mewo黑色素瘤细胞脑转移基于这些初步结果，我们假设黑色素瘤中AMPKα2的失活促进肿瘤的发生进展为黑色素瘤脑转移。在目标1中，我们将确定AMPKα2在黑色素瘤脑中的作用使用小鼠模型和人类样本进行转移。我们计划表征AMPKα2缺失的影响无论是同基因小鼠模型还是基因工程小鼠模型。人黑色素瘤脑转移标本将用于通过空间单细胞α-SEQ分析来探索AMPKRNA2缺失的贡献。在目标2中，我们将表征参与黑色素瘤脑转移代谢调节的AMPK下游靶点。我们将研究一种新的AMPKα2底物在从头脂肪生成中的作用。在我们的初步研究中确定，黑色素瘤脑转移，并探索其他新的AMPKα2靶点通过对小鼠模型的肿瘤样本进行全面的代谢组学和RPPA分析。在目标3中，我们将评估针对AMPK通路的代谢性药物在增强人黑色素瘤同种异种移植瘤脑转移的靶向和免疫治疗以及基因工程小鼠模型。为了实现这些目标，我们组建了一支调查小组拥有多种专业知识，包括癌细胞代谢、黑色素瘤脑转移生物学、黑色素瘤肿瘤学家/外科医生和计算生物学。我们的研究不仅将为我们提供对黑色素瘤脑转移中的AMPK代谢信号解决了该领域的一个重大知识缺口，但也找出针对黑色素瘤脑转移的新的治疗方法。