Copper-mediated metabolic reprogramming and ECM alterations in TNBC metastasis

三阴性乳腺癌(TNBC)患者面临着巨大的临床挑战，因为他们 表现出较高的转移性复发率，对可用的靶向治疗反应较差。 鉴于其临床意义，开发有效的靶向抗转移药物势在必行。 治疗TNBC的治疗方法。金属是肿瘤促进途径的辅助因素 靶向金属使这些通路失效已经成为一种潜在的抗癌疗法 策略。铜是一种必需的微量元素，它是一种催化辅因子 有助于肿瘤血管生成和转移的金属酶/蛋白质。此外, 恶性细胞对铜的摄取增加导致了铜特异性 作为治疗剂的螯合剂。在一个潜在的变革性发现中，我们发现了 在原发肿瘤内，有一群高度转移的OCT4+SOX2+细胞。我们 表明这些转移细胞的细胞内铜和铜的水平显著升高 对铜缺乏表现出更高的敏感性。我们还表明，铜的枯竭 改变小鼠和人肺转移瘤中细胞外基质的结构。 我们的中心假设是铜对转移的两个关键方面有贡献：癌细胞 直接导致转移的内在代谢途径；以及“转移前生态位” 这支持了播散性转移肿瘤细胞的定植和生长。为了测试这一点 假设，我们将使用临床前模型来阐明细胞和分子机制。 口服铜络合剂四硫代钼酸(TM)和杠杆来自我们完成的银行样本 第二阶段TM临床试验，以开发胶原重塑产品作为TM反应的生物标志物。 这项提议的中心目标是理解铜枯竭的机制基础 针对TNBC转移的可行治疗方法。我们预计将取得重大进展 通过以下目标。目标1将建立铜介导的 TNBC的代谢再编程和转移及其关键细胞和分子的解剖 机制，目标2将研究铜缺乏如何重新编程细胞外 基质在远端转移的器官中产生不适宜居住的微环境以损害 并开发对TM有反应的临床有价值的生物标记物。基本原理 来自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推进到更大的随机试验中，但为了确定新的铜离子通路 针对TNBC的新治疗策略的开发。

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.