Understanding lactate catabolism by BACH1 in triple negative breast cancer

了解三阴性乳腺癌中 BACH1 的乳酸分解代谢

基本信息

批准号：
10672893
负责人：
Jiyoung Lee
金额：
$ 48.83万
依托单位：
GEORGE WASHINGTON UNIVERSITY
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672893
关键词：
Acute Intermittent Porphyria Animal Model Antineoplastic Agents BACH1 gene Binding Biochemical Pathway Biological Assay Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Cancer Cell Growth Carbon Catabolism Cells Cellular biology Clinical Data Clinical Research Combined Modality Therapy Consumption Data Dependence Development Drug Design Drug Targeting Enzymes FDA approved Gene Expression Genes Genetic Genetic Transcription Goals Hemin Heterogeneity In Vitro Individual Label Lactate Dehydrogenase Lactate Transporter Link Malignant Neoplasms Mammary Neoplasms Messenger RNA Metabolic Metabolic Pathway Metabolism Mitochondria Molecular Molecular Biology Mus Nature Neoplasm Metastasis Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Play Population Predisposition Publishing Regulation Repression Research Research Personnel Research Proposals Respiration Role Source Testing Therapeutic Therapeutic Intervention Transcript Transcription Repressor Transcriptional Regulation Work anti-cancer anti-cancer therapeutic biochemical tools cancer cell cancer therapy clinically significant gene repression heme a improved in vivo inhibitor innovation insight mRNA Expression malignant breast neoplasm metabolic phenotype metabolomics mitochondrial metabolism mouse model multidisciplinary neoplastic cell novel novel strategies oxidation patient derived xenograft model pharmacologic programs pyruvate carrier response single-cell RNA sequencing skills small hairpin RNA targeted treatment therapeutic target therapeutically effective tool transcription factor transcriptomics triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor metabolism

项目摘要

PROJECT SUMMARY Primary metabolic pathways in cancer are useful targets for therapeutic intervention. However, intratumoral heterogeneity in cancer metabolism is a major challenge for anti-cancer therapy. Reducing metabolic variance by reprogramming cancer metabolism is essential to enhance efficacy of inhibitors targeting metabolism. Our long-term goal is to overcome metabolic heterogeneity through reprogramming metabolic networks to increase the number of cancer cells vulnerable to metabolic inhibitors. To reach this goal, our novel strategy is to reduce metabolic variance among cancer cells by targeting BACH1, a master regulator of metabolism-related transcription in triple negative breast cancer (TNBC), to obtain maximal response of drugs targeting metabolic pathways. Our previous molecular and metabolomic profiling of breast tumors revealed that BACH1 suppresses mitochondrial metabolism. Thus, BACH1 depletion made TNBC cells more sensitive to mitochondrial inhibitors. These findings led to the novel concept that BACH1 depletion increases the proportion of cancer cells with higher dependency on mitochondrial respiration and restricted tumor metabolic plasticity. Our preliminary studies indicate that BACH1 also suppresses lactate catabolism, which is a primary pathway for lactate oxidation in mitochondria of cancer cells. In support of this finding, recent clinical studies showed that lactate catabolism depends on lactate transporter (MCT1). In TNBC cells, BACH1 represses transcription of genes that encode enzymes involved in lactate catabolism, including lactate transporter (MCT1), lactate dehydrogenase B (LDHB), and mitochondrial pyruvate carriers. Specifically, BACH1 depletion sensitized cancer cells to blockade of MCT1 or LDHB. Based on our preliminary data, we hypothesize that BACH1 is the key determinant of whether cancer cells produce lactate or consume lactate. The primary objective of this proposed study is to link BACH1 contribution to lactate catabolic variance, and to better understand regulation of lactate oxidation in TNBC. Using multiple innovative approaches, including in vitro and in vivo breast tumor models and a combination of transcriptomics and metabolomics, we will interrogate BACH1 regulation of lactate catabolism and define the underlying molecular regulatory mechanism in breast cancer cells. Furthermore, using patient-derived xenograft and syngeneic mouse models, we will investigate whether BACH1 inhibition (through the repurposed non-toxic FDA-approved drug, panhematin) increases breast tumor vulnerability to drugs targeting the lactate transporter MCT1. By combining cell biology and in vivo assays, this study will provide comprehensive insights into how cancer cells use lactate as a substrate, whether metabolic variances are reduced by targeting BACH1, and how to achieve better therapeutic strategies using lactate catabolism inhibitors.

项目概要癌症的主要代谢途径是治疗干预的有用目标。然而，瘤内癌症代谢的异质性是抗癌治疗的主要挑战。减少代谢差异通过重新编程癌症代谢对于增强靶向代谢的抑制剂的功效至关重要。我们的长期目标是通过重新编程代谢网络来克服代谢异质性，以增加易受代谢抑制剂影响的癌细胞数量。为了实现这一目标，我们的新策略是减少通过靶向 BACH1（代谢相关的主要调节因子）来改变癌细胞的代谢差异三阴性乳腺癌 (TNBC) 中的转录，以获得靶向代谢药物的最大反应途径。我们之前对乳腺肿瘤的分子和代谢组学分析表明，BACH1 抑制线粒体代谢。因此，BACH1 缺失使 TNBC 细胞对线粒体抑制剂更加敏感。这些发现引出了一个新概念：BACH1 缺失会增加具有较高水平的癌细胞比例。对线粒体呼吸的依赖性和受限的肿瘤代谢可塑性。我们的初步研究表明 BACH1 还抑制乳酸分解代谢，这是乳酸氧化的主要途径癌细胞的线粒体。为了支持这一发现，最近的临床研究表明乳酸分解代谢取决于乳酸转运蛋白 (MCT1)。在 TNBC 细胞中，BACH1 抑制编码基因的转录参与乳酸分解代谢的酶，包括乳酸转运蛋白 (MCT1)、乳酸脱氢酶 B (LDHB)、和线粒体丙酮酸载体。具体来说，BACH1 缺失使癌细胞对 MCT1 的阻断变得敏感或LDHB。根据我们的初步数据，我们假设 BACH1 是癌症是否发生的关键决定因素细胞产生乳酸或消耗乳酸。这项拟议研究的主要目标是将 BACH1 连接起来对乳酸分解代谢变化的贡献，并更好地了解 TNBC 中乳酸氧化的调节。使用多种创新方法，包括体外和体内乳腺肿瘤模型以及组合转录组学和代谢组学，我们将探讨 BACH1 对乳酸分解代谢的调节并定义乳腺癌细胞的潜在分子调控机制。此外，使用患者来源的异种移植物和同基因小鼠模型，我们将研究是否 BACH1 抑制（通过重新利用的无毒 FDA 批准的药物 panhematin）增加了乳腺肿瘤对针对乳酸转运蛋白的药物的脆弱性 MCT1。通过结合细胞生物学和体内测定，这项研究将提供关于如何癌细胞使用乳酸作为底物，是否可以通过靶向 BACH1 来减少代谢差异，以及如何减少代谢差异使用乳酸分解代谢抑制剂实现更好的治疗策略。