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: 10398970
• 负责人: Vivek Mittal
• 金额: $ 53.53万
• 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/10398970
• 关键词: 5' -AMP-activated protein kinase; 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; Investigation; LOXL2 gene; Link; Lung; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metals; Mitochondria; Modality; Molecular; Molecular Chaperones; Mus; Neoplasm Metastasis; Oral; Organ; Outcome; Pathway interactions; Patients; Pharmacology; Phase; Phase II Clinical Trials; Phenotype; Population; Pre-Clinical Model; Primary Neoplasm; Progression-Free Survivals; Protein Kinase; Protein-Lysine 6-Oxidase; Proteins; Randomized Clinical Trials; Recurrence; Reporting; Role; Sampling; Serum; Signal Transduction; Testing; Therapeutic; Therapeutic Agents; Trace Elements; Tumor Angiogenesis; Work; amine oxidase; anti-cancer therapeutic; base; 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; pre-clinical; prevent; randomized trial; response; response biomarker; second harmonic generation imaging; stem cells; targeted treatment; tetrathiomolybdate; thiomolybdate; triple-negative invasive breast carcinoma; tumor; 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.

三阴性乳腺癌 (TNBC) 患者面临着巨大的临床挑战，因为他们 表现出较高的转移复发率，并且对现有靶向治疗的反应较差。 鉴于临床意义，开发有效的靶向抗转移药物势在必行 用于治疗 TNBC 的疗法。金属作为肿瘤促进途径的辅助因子 靶向金属来禁用这些途径已成为一种潜在的抗癌疗法 战略。铜是一种重要的微量元素，可作为许多物质的催化辅助因子 有助于肿瘤血管生成和转移的金属酶/蛋白质。此外， 恶性细胞对铜的吸收增加导致了铜特异性的发展 螯合剂作为治疗剂。在一项潜在的变革性发现中，我们发现 在原发肿瘤内，高度转移的 OCT4+ SOX2+ 细胞的离散群体。我们 表明这些转移细胞的细胞内铜水平显着升高，并且 对缺铜的敏感性增加。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“转移前生态位” 支持播散性转移性肿瘤细胞的定植和生长。为了测试这个 假设，我们将使用临床前模型来阐明细胞和分子机制 口服铜螯合剂四硫代钼酸盐 (TM) 并利用我们已完成的库存样品 II 期 TM 临床试验，开发胶原蛋白重塑产品作为 TM 反应的生物标志物。 该提案的中心目标是了解铜耗竭的机制基础 针对 TNBC 转移的可行治疗方法。我们期望取得重大进展 通过以下目标。目标 1 将建立铜介导之间的直接联系 TNBC 中的代谢重编程和转移并剖析关键细胞和分子 机制，目标 2 将研究铜缺乏如何重新编程细胞外 远端转移器官中的基质产生不适宜的微环境以损害 转移并开发有临床价值的 TM 反应生物标志物。基本的 这些综合药理学和遗传学研究的发现有可能不 只是为了将 TM 推进到更大规模的随机试验中，而是为了确定新的铜途径 开发针对 TNBC 的新治疗策略。