Role of necrosis in the evolution of highly metastatic and chemo-resistant breast cancers

高级别、快速生长的乳腺癌通常表现为坏死，通常在肿瘤内部， 那里的灌流、营养和氧气都是有限的。最近的研究表明，坏死并不是 这不仅是侵袭性疾病的指标，也是侵袭性表型的调节因素，通过 阻碍癌症药物的传递，促进基因组进化，并促进远处转移 器官。然而，我们目前对调节坏死的分子机制缺乏了解。 发展，因此，没有治疗方法来防止坏死的发展和其 下游对肿瘤侵袭的影响。对于这一应用，我们开发了动物模型， 能够在坏死的内部对肿瘤宿主生态系统进行强有力的解剖。我们的研究 发现一种分泌蛋白，血管生成素样蛋白7(Angptl7)，是由邻近的肿瘤细胞产生的 是肿瘤核心血管发育的调节器。重要的是，当 Angptl7在基因上受到抑制，肿瘤坏死、肿瘤生长和转移转移 每一个都大大减少了。因此，坏死的发展不是不可避免的，而是可以通过以下方式预防的 血管紧张素转换酶7抑制。在拟议的工作中，我们将结合使用创新动物模型的研究 并对乳腺癌患者的血液和组织样本进行检验的假说 坏死是高转移性和耐药乳腺肿瘤演变的驱动力 细胞。在目标1中，我们将使用小鼠模型来检验Angptl7导致坏死的假设 限制化疗药物向肿瘤核心的输送，并且Angptl7抑制发挥协同作用 使用新辅助化疗药物，以改善药物输送和提高肿瘤杀伤力。在目标2中，我们 将使用大量基于人群的早期乳腺癌患者的组织来 确定血管扩张是血管紧张素转换酶7诱导的坏死的一个指标，如何影响血管紧张性心脏病的风险 局部和远处转移转移预测辅助治疗的益处。在目标3中，我们 将在一种创新的大鼠模型中应用基因组测序和循环肿瘤DNA分析 液体活检研究，以确定与Angptl7诱导的坏死相关的基因组特征。 然后，我们将确定循环中的肿瘤DNA签名的坏死对预后的影响 人类临床样本。这项工作将把坏死发育定义为肿瘤的引擎 多样化和攻击性以及早期和转移性的临床背景 预防坏死可以使乳腺癌和肿瘤类型的患者受益的环境。

High-grade, fast-growing breast cancers often display necrosis, usually within the tumor interior, where perfusion, nutrients, and oxygen are limited. Recent studies indicate that necrosis is not just an indicator of aggressive disease, but also a regulator of the aggressive phenotype, by impairing cancer drug delivery, promoting genomic evolution, and instigating metastasis to distant organs. However, we currently lack an understanding of the molecular mechanisms regulating necrosis development and consequently, there are no therapies to prevent the development of necrosis and its downstream effects on tumor aggression. For this application, we have developed animal models that enable the robust dissection of the tumor-host ecosystem in the necrotic interior. Our studies reveal that a secreted protein, angiopoietin-like 7 (Angptl7), is produced by tumor cells adjacent to the necrotic core and is a regulator of tumor core vasculature development. Importantly, when Angptl7 is suppressed genetically, tumor necrosis, tumor growth, and metastatic dissemination are each drastically reduced. Thus, necrosis development is not inevitable but rather is preventable by Angptl7 suppression. In the proposed work, we will combine studies using innovative animal models and breast cancer patient blood and tissue samples to test the hypothesis that the development of necrosis is a driving force for the evolution of highly metastatic and drug-resistant breast tumor cells. In Aim 1, we will use mouse models to test the hypothesis that Angptl7-induced necrosis limits delivery of chemotherapeutics to the tumor core, and that Angptl7 suppression synergizes with neoadjuvant chemotherapeutics to improve drug delivery and improve tumor killing. In Aim 2, we will use tissue from a large population-based cohort of early-stage breast cancer patients to determine how dilated blood vessels, an indicator of Angptl7-induced necrosis, influences risk of local and distant metastatic dissemination to predict benefit from adjuvant therapy. In Aim 3, we will apply genomic sequencing and circulating tumor DNA analysis in an innovative rat model for liquid biopsy studies to define the genomic signatures associated with Angptl7-induced necrosis. We will then determine the prognostic impact of a circulating tumor DNA signature of necrosis in human clinical samples. This work will define necrosis development as an engine for tumor diversification and aggression, and the clinical contexts both in early stage and metastatic settings where necrosis prevention could benetits patients with breast cancer and tumor types.