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Copper-mediated metabolic reprogramming and ECM alterations in TNBC metastasis

TNBC 转移中铜介导的代谢重编程和 ECM 改变

基本信息

批准号：
10617710
负责人：
Vivek Mittal
金额：
$ 53.54万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617710
关键词：
5&apos -AMP-activated protein kinase Ablation Affect Animal Model Architecture Atomic Force Microscopy Binding Bioenergetics Biological Markers Breast Cancer Patient Breast cancer metastasis Cells Chelating Agents Clinical Clinical Trials Collagen Copper Deposition Development Disease Distal ERBB2 gene Enzymes Exhibits Extracellular Matrix FRAP1 gene Future Genetic Glycolysis Goals Human Impairment Invaded Investigation LOXL2 gene Link Lung Measures Mediating Metabolic Metabolic Pathway Metabolism Metals Metastatic/Recurrent Mitochondria Modality Molecular Molecular Chaperones Mus Neoplasm Metastasis Oral Organ Outcome Pathway interactions Patients Phase Phase II Clinical Trials Phenotype Population Pre-Clinical Model Primary Neoplasm Progression-Free Survivals Protein-Lysine 6-Oxidase Proteins Reporting Role Sampling Serum Signal Transduction Testing Therapeutic Therapeutic Agents Trace Elements Tumor Angiogenesis Tumor Promotion Work amine oxidase anti-cancer therapeutic cancer cell clinically significant cofactor combat complex IV crosslink effective therapy genetic approach genetic manipulation high risk human data hypocupremia metabolic phenotype metabolomics metalloenzyme mouse model mutant neoplastic cell novel novel therapeutic intervention patient subsets pharmacologic pre-clinical prevent programs randomized trial randomized, clinical trials response response biomarker second harmonic generation imaging stem cells targeted treatment tetrathiomolybdate thiomolybdate triple-negative invasive breast carcinoma tumor microenvironment uptake

项目摘要

Triple negative breast cancer (TNBC) patients present a formidable clinical challenge, as they exhibit higher rates of metastatic recurrence, and respond poorly to available targeted therapies. Given the clinical significance, it is imperative to develop effective targeted anti-metastatic therapies for the treatment of TNBC. Metals serve as co-factors for tumor promoting pathways and targeting metals to disable these pathways has emerged as a potential anti-cancer therapeutic strategy. Copper, an essential trace element functions as a catalytic cofactor for a host of metalloenzymes/proteins that contribute to tumor angiogenesis and metastasis. In addition, increased copper uptake by malignant cells has led to the development of copper-specific chelators as therapeutic agents. In a potentially transformative discovery, we have identified within the primary tumor, a discrete population of highly metastatic OCT4+ SOX2+ cells. We show that these metastatic cells have significantly elevated levels of intracellular copper and exhibit increased sensitivity to copper deficiency. We have also shown that copper depletion alters the architecture of extracellular matrix in the metastatic lungs of both mouse and human. Our central hypothesis is that copper contributes to two key aspects of metastasis: cancer cell intrinsic metabolic pathways that directly contribute to metastasis; and the “pre-metastatic niche” that supports colonization, and outgrowth of disseminated metastatic tumor cells. To test this hypothesis, we will use pre-clinical models to elucidate cellular and molecular mechanisms of oral copper chelator tetrathiomolybdate (TM) and leverage banked samples from our completed phase II TM clinical trial to develop collagen remodeling products as biomarkers of TM response. The central goal of this proposal is to understand the mechanistic basis of copper depletion as a viable treatment approach against TNBC metastasis. We expect to make significant advances through the following aims. Aim 1 will establish the direct link between copper-mediated metabolic reprograming and metastasis in TNBC and dissect key cellular and molecular mechanisms, and Aim 2 will investigate how copper deficiency reprograms the extracellular matrix in the distal metastatic organs to generate an inhospitable microenvironment to impair metastasis and develop clinically valuable biomarkers of response to TM. Fundamental discoveries from these integrated pharmacological and genetic investigations has the potential not only to advance TM into larger randomized trials, but to identify new copper pathways for the development of novel therapeutic strategies against TNBC.

三阴性乳腺癌（TNBC）患者面临着巨大的临床挑战

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.

DOI：
10.1038/s41467-021-27559-z
发表时间：
2021-12-15
期刊：
Nature communications
影响因子：
16.6
作者：
Ramchandani D;Berisa M;Tavarez DA;Li Z;Miele M;Bai Y;Lee SB;Ban Y;Dephoure N;Hendrickson RC;Cloonan SM;Gao D;Cross JR;Vahdat LT;Mittal V
通讯作者：
Mittal V