ATF4-SCD axis in bone metastatic prostate cancer

骨转移性前列腺癌中的 ATF4-SCD 轴

• 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
• 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

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 骨转移疾病与前列腺癌(PCa)患者的发病率和死亡率增加相关。 各种研究，包括我们自己的研究，已经确定骨髓利基在治疗过程中起支持作用 转移进展，这导致肿瘤细胞存活率增加和逃避治疗，但分子 机制还没有完全弄清楚。我们之前的研究强调了脂肪细胞，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者和其侵袭性表型的贡献者。 我们已经证明，脂肪细胞提供的脂类，在脂肪细胞-肿瘤细胞串扰时释放，诱导促- 存活表型和促进内质网和氧化应激激活作为潜在的细胞适应机制 PCa细胞。我的新的初步数据现在发现了肿瘤细胞-脂肪细胞的新的分子后果 串扰，包括以下：1)激活前列腺癌细胞对脂质过氧化的适应性反应 由脂肪细胞提供的脂类介导；2)ER应激基因ATF4的表达增强与脂质去饱和化 PCa细胞中的SCD酶可能是抵抗脂质过氧化损伤的一种防御机制；3) 内质网应激基因ATF4在调节脂质环境下生长的PCa细胞中SCD水平和活性方面发挥潜在作用。 丰富的条件；4)脂肪细胞提供的脂质可能参与调节肿瘤代谢物。 基于这些发现，这一提议的中心假设是脂肪细胞激活ATF4- SCD轴调节肿瘤代谢，促进PCa在骨中的存活。 我提出了一种多方面的方法，包括细胞培养和小鼠脂肪分解模型，体内模型 肿瘤的生长，以及最先进的RNAseq和代谢组学方法来确定其作用 先前未知的ATF4-SCD轴在调节肿瘤代谢和促进骨骼进展中的作用。 这些研究将在两个目标下进行。在目标1中，我将利用脂肪分解缺陷的小鼠并创造出人类 和稳定敲除ATF4的小鼠前列腺癌细胞研究脂肪细胞供应的脂类在调控中的作用 ATF4-ER应激反应通路促进骨骼进展。在目标2中，我将重点介绍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这种激活是如何 轴心改变肿瘤代谢物。总之，这项研究的结果将被用来描绘关键分子 转移性前列腺癌细胞参与ATF4和SCD在富脂骨髓中存活的机制。这 这项工作还可能揭示针对肿瘤新陈代谢的潜在新选择，以改进治疗和/或 预防侵袭性疾病。这项拟议的工作将对多种癌症类型产生广泛的影响。 转移到骨骼或由骨骼产生并可能受骨髓脂肪影响的肿瘤 组织。