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

• 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
• 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' -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

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.

三重阴性乳腺癌（TNBC）患者提出了巨大的临床挑战 暴露于更高的转移性复发率，对可用的靶向疗法的反应较差。 鉴于临床意义，必须开发有效的靶向抗转移性 治疗TNBC的疗法。金属是促进途径的副因素 靶向金属禁用这些途径已成为潜在的抗癌治疗 战略。铜，必不可少的痕量元素作为宿主的催化辅因子 有助于肿瘤血管生成和转移的金属酶/蛋白质。此外， 恶性细胞增加铜的吸收已导致铜特异性的发展 螯合剂作为治疗剂。在潜在的变革性发现中，我们已经确定了 在原发性肿瘤中，高度转移性OCT4+ SOX2+细胞的离散群体。我们 表明这些转移细胞具有明显升高的细胞内铜和 对铜缺乏症的敏感性提高。我们还表明铜耗尽 改变小鼠和人类转移性肺中细胞外基质的结构。 我们的中心假设是铜有助于转移的两个关键方面：癌细胞 直接导致转移的内在代谢途径；和“前转移的利基市场” 这支持了定殖和传播转移性肿瘤细胞的生长。测试这个 假设，我们将使用临床前模型来阐明 口服铜螯合剂四甲酸酯（TM），并从我们完成的 II期TM临床试验，以开发胶原蛋白重塑产物作为TM反应的生物标志物。 该提案的核心目标是将铜部署的机械基础视为 对TNBC转移的可行治疗方法。我们希望取得重大进步 通过以下目标。 AIM 1将建立铜介导的直接联系 TNBC中的代谢重编程和转移，并剖析钥匙细胞和分子 机理和AIM 2将研究铜缺乏如何重新编程细胞外 远端转移器官中的矩阵，产生一个不良的微环境以损害 转移并发展出对TM的临床有价值的生物标志物。基本的 这些综合药物和遗传研究中的发现具有潜力 只是将TM推进大型随机试验，但要确定新的铜途径 开发针对TNBC的新型治疗策略。

项目成果

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