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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：
10567049
负责人：
Vashisht G Yennu Nanda
金额：
$ 49.92万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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 2023-08-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10567049
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.

项目概要： AMP 激活蛋白激酶 (AMPK) 是一种重要的进化保守能量传感器，可调节通过监测细胞内 AMP 或 ADP 与 ATP 比率的变化来维持能量稳态。越来越多的证据支持 AMPK 通路是代谢和癌症界面的主要信号传导者之一。然而，AMPK 在肿瘤进展和转移中的作用仍不清楚。我们最近的分析黑色素瘤癌症基因组学数据显示，编码 α 的 PRKAA2 基因发生突变 AMPK 的 2 催化亚基，出现在 8-10% 的皮肤黑色素瘤中，并且往往与 NF1 突变同时发生。在我们的初步研究中，我们发现 AMPKα2 的敲除促进了锚定独立的生长软琼脂测定中突变的 NF1-黑色素瘤细胞及其在裸鼠中作为异种移植肿瘤的生长。重要的是，我们发现人黑色素瘤脑中 AMPKα2 的表达显着下调转移样本与患者匹配的颅外转移样本进行比较。此外，淘汰赛 AMPKα2 促进 NF1 突变 Mewo 黑色素瘤细胞在裸鼠体内的脑转移。基于这些初步结果，我们假设黑色素瘤中 AMPKα2 失活促进肿瘤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。我们计划描述 AMPKα2 损失的影响同基因和基因工程小鼠模型。人类黑色素瘤脑转移样本将被用于通过空间单细胞 RNA-seq 分析探索 AMPKα2 丢失的影响。在目标 2 中，我们将描述参与黑色素瘤脑转移代谢调节的 AMPK 下游靶标。我们将研究 AMPKα2 的新型假定底物在从头脂肪生成中的贡献，我们的初步研究中确定了黑色素瘤脑转移，并探索其他新的 AMPKα2 靶点通过对小鼠模型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 途径的代谢药物对增强疗效的治疗效果使用人类黑色素瘤异种移植物、同基因的黑色素瘤脑转移的靶向和免疫疗法和基因工程小鼠模型。为了实现这些目标，我们组建了一个研究小组拥有各种专业知识，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的作用提供重要的见解黑色素瘤脑转移中的 AMPK 代谢信号解决了该领域的重大知识空白，但是还确定了针对黑色素瘤脑转移的新治疗方法。