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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.

项目总结