ATF4-SCD axis in bone metastatic prostate cancer

骨转移性前列腺癌中的 ATF4-SCD 轴

基本信息

批准号：
10748863
负责人：
Alexis Rylee Wilson
金额：
$ 4.53万
依托单位：
WAYNE STATE UNIVERSITY
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：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748863
关键词：
Address Adipocytes Adipose tissue Affect Age Amino Acids Aspartate-Ammonia Ligase Bone Marrow Cancer Patient Cell Communication Cell Culture Techniques Cell Death Cell Energetics Cell Line Cell Survival Cell model Cells Cessation of life Chemoresistance Coculture Techniques Data Defense Mechanisms Detection Disease Endoplasmic Reticulum Enzymes Exposure to Future Genes Glutamine Growth Homeostasis Human In Vitro Incidence Inflammatory Link Lipase Lipid Mobilization Lipid Peroxidation Lipids Lipolysis Malignant neoplasm of prostate Marrow Mediating Metabolic Metabolism Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Molecular Target Morbidity - disease rate Mus Obesity Oxidative Stress Pathway interactions Phenotype Play Prevention Research Role Signal Transduction Site Stearoyl-CoA Desaturase Stress Testing Tumor Promotion Work arm biological adaptation to stress bone cancer survival cancer type cell growth cell type chemotherapy docetaxel endoplasmic reticulum stress improved in vivo in vivo Model knock-down metabolome metabolomics mortality mouse model neoplastic cell new therapeutic target novel palliative pharmacologic prostate cancer cell prostate cancer metastasis response skeletal disorder stem transcriptome sequencing tumor tumor growth tumor metabolism tumor progression

项目摘要

Project Summary Bone metastatic disease correlates with increased morbidity and mortality in prostate cancer (PCa) patients. Various studies, including our own, have determined that the bone marrow niche plays a supportive role during metastatic progression, which leads to increased tumor cell survival and escape from therapy, but the molecular mechanisms are not fully understood. Our previous studies have highlighted adipocytes, an abundant cell type in the bone marrow, as key modulators of tumor cell energetics and contributors to their aggressive phenotype. We have demonstrated that adipocyte-supplied lipids, released upon adipocyte-tumor cell crosstalk, induce pro- survival phenotype and promote ER and oxidative stress activation as potential cell adaptation mechanisms in PCa cells. My new preliminary data have now uncovered novel molecular consequences of tumor cell-adipocyte crosstalk, including the following: 1) Activation of an adaptive response to lipid peroxidation in PCa cells is mediated by adipocyte-supplied lipids; 2) Augmented expression of ER stress gene, ATF4, and lipid desaturation enzyme, SCD, in PCa cells is a possible defense mechanism against damaging effects of lipid peroxidation; 3) ER stress gene, ATF4, plays a potential role in regulating SCD levels and activity in PCa cells grown under lipid- rich conditions; and 4) Adipocyte-supplied lipids are likely involved in regulating the tumor metabolome. Stemming from these findings, the central hypothesis of this proposal is that adipocyte activation of the ATF4- SCD axis modulates tumor metabolism to promote the survival of PCa in bone. I propose a multi-faceted approach that includes cell culture and mouse models of lipolysis, in vivo models of intratibial tumor growth, as well as state-of-the-art RNAseq and metabolomics approaches to determine the role of previously unexplored ATF4-SCD axis in regulating tumor metabolism and promoting progression in bone. These studies will be performed in two aims. In Aim 1, I will utilize mice deficient in lipolysis and create human and murine PCa cells with stable knockdown of ATF4 to study the role of adipocyte-supplied lipids in modulating the ATF4-ER stress response pathway to promote progression in bone. In Aim 2, I will focus on the ATF4-SCD interaction and utilize RNA-seq and metabolomics approaches to determine how lipid-mediated activation of this axis alters tumor metabolome. Altogether, the results of this study will be used to delineate key molecular mechanisms by which metastatic PCa cells engage ATF4 and SCD to survive in the lipid-rich bone marrow. This work will also likely reveal potential novel options for targeting tumor metabolism for improved therapy and/or prevention of aggressive disease. This proposed work will have broad implications for numerous cancer types that metastasize to bone or those that arise from bone and are likely to be affected by the bone marrow adipose tissue.

项目摘要骨转移性疾病与前列腺癌（PCA）患者的发病率和死亡率的增加相关。包括我们自己在内的各种研究都确定骨髓小裂在转移性进展，导致肿瘤细胞的存活增加并从治疗中逃脱，但是分子机制尚未完全理解。我们以前的研究突出了脂肪细胞，一种丰富的细胞类型在骨髓中，作为肿瘤细胞能量的关键调节剂，以及其侵袭性表型的贡献者。我们已经证明，在脂肪细胞 - 肿瘤细胞串扰上释放的脂肪细胞供脂质，诱导促脂质生存表型并促进ER和氧化应激激活作为潜在的细胞适应机制 PCA细胞。我的新初步数据现在发现了肿瘤细胞 - 脂肪细胞的新分子后果串扰，包括以下内容：1）激活PCA细胞中脂质过氧化的自适应反应是由脂肪细胞供应的脂质介导； 2）增强ER应激基因，ATF4和脂质去饱和的表达 PCA细胞中的酶，SCD是防御脂质过氧化作用的一种防御机制。 3） ER应激基因ATF4在调节脂质下生长的PCA细胞的SCD水平和活性中起着潜在的作用丰富的条件；和4）脂肪细胞供应的脂质可能参与调节肿瘤代谢组。出于这些发现，该提议的核心假设是ATF4--的脂肪细胞激活 SCD轴调节肿瘤代谢以促进PCA在骨骼中的存活。我提出了一种多面方法，包括细胞培养和脂解的小鼠模型，体内模型肿瘤内肿瘤的生长以及最先进的RNASEQ和代谢组学方法来确定作用以前未探索的ATF4-SCD轴在调节肿瘤代谢和促进骨骼进展方面的表现。这些研究将以两个目标进行。在AIM 1中，我将利用缺乏脂解的小鼠并创造人和鼠PCA细胞具有稳定的ATF4敲低的细胞，以研究脂肪细胞培养的脂质在调节中的作用促进骨骼进展的ATF4-ER应力反应途径。在AIM 2中，我将专注于ATF4-SCD 相互作用并利用RNA-seq和代谢组学方法来确定脂质介导的激活如何轴改变肿瘤代谢组。总之，这项研究的结果将用于描述钥匙分子转移性PCA细胞参与ATF4和SCD以在富含脂质的骨髓中生存的机制。这工作还可能揭示靶向肿瘤代谢以改善治疗和/或的潜在新颖选择预防侵略性疾病。这项拟议的工作将对多种癌症类型产生广泛的影响转移到骨头或由骨骼产生的骨骼转移，可能会受到骨髓脂肪的影响组织。