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

坏死在高度转移性和化疗耐药性乳腺癌演变中的作用

• 批准号: 10736486
• 负责人: Kevin Jon Cheung
• 金额: $ 64.2万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736486
• 关键词: Adjuvant; Adjuvant Therapy; Aftercare; Aggressive behavior; Aneuploidy; Angiopoietins; Animal Model; Antineoplastic Agents; Benefits and Risks; Biological Availability; Biological Models; Blood; Blood Vessels; Blood flow; Blood specimen; Breast Cancer Cell; Breast Cancer Detection; Breast Cancer Patient; Breast Cancer therapy; Breast cancer metastasis; Cell Death; Cells; Cessation of life; Chemoresistance; Clinical; Complex; DNA analysis; Data; Development; Diagnosis; Disease; Dissection; Distant; Drug Delivery Systems; Drug resistance; Ecosystem; Epidemiologist; Evolution; Family; Generations; Genes; Genome; Genomics; Hand; Heterogeneity; Histologic; Human; Hypoxia; Impairment; Individual; Malignant Neoplasms; Mammary Neoplasms; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Modeling; Molecular; Mus; Mutate; Mutation; Necrosis; Necrosis Induction; Neoadjuvant Therapy; Neoplasm Metastasis; Nutrient; Organ; Outcome; Oxygen; Patients; Penetration; Perfusion; Pharmaceutical Preparations; Phenotype; Population Study; Prevention; Primary Neoplasm; Prognostic Marker; Protein Secretion; Rattus; Recurrence; Recurrent Malignant Neoplasm; Residual Cancers; Resistance; Risk; Risk Factors; Risk Reduction; Role; Sampling; Source; Testing; Therapeutic; Tissue Sample; Tissues; Toxic effect; Tumor-Derived; Woman; Work; aggressive therapy; barrier to testing; cancer recurrence; cancer subtypes; cancer therapy; chemotherapy; clinical prognostic; cohort; driving force; drug development; genomic signature; improved; innovation; knock-down; liquid biopsy; malignant breast neoplasm; member; molecular marker; mouse model; neoplastic cell; patient derived xenograft model; population based; prevent; prognostic; prognostication; programs; response; risk prediction; synergism; therapeutic development; therapy development; therapy resistant; trait; tumor; tumor DNA; tumor growth; tumor heterogeneity

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.

高级别、快速生长的乳腺癌通常表现出坏死，通常在肿瘤内部， 灌注、营养和氧气有限的地方。最近的研究表明，坏死并不 不仅是侵袭性疾病的指标，也是侵袭性表型的调节因子 损害癌症药物输送，促进基因组进化，并引发远处转移 器官。然而，我们目前对调节坏死的分子机制缺乏了解。 因此，没有任何疗法可以阻止坏死及其发展 对肿瘤侵袭的下游影响。对于这个应用，我们开发了动物模型 能够对坏死内部的肿瘤宿主生态系统进行强有力的解剖。我们的研究 揭示了一种分泌蛋白，血管生成素样 7 (Angptl7)，是由邻近的肿瘤细胞产生的 至坏死核心，并且是肿瘤核心脉管系统发育的调节者。重要的是，当 Angptl7 受到基因抑制，肿瘤坏死、肿瘤生长和转移播散均受到抑制。 均大幅减少。因此，坏死的发展并非不可避免，而是可以通过以下方式预防： Angptl7 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 和乳腺癌患者的血液和组织样本来检验以下假设： 坏死是高度转移和耐药性乳腺肿瘤进化的驱动力 细胞。在目标 1 中，我们将使用小鼠模型来检验 Angptl7 诱导坏死的假设 限制化疗药物向肿瘤核心的输送，并且 Angptl7 抑制具有协同作用 与新辅助化疗一起改善药物输送并提高肿瘤杀灭能力。在目标 2 中，我们 将使用来自大量早期乳腺癌患者群体的组织来 确定扩张的血管（Angptl7 诱导坏死的指标）如何影响风险 局部和远处转移扩散以预测辅助治疗的益处。在目标 3 中，我们 将在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肿瘤 DNA 坏死特征对预后的影响 人类临床样本。这项工作将把坏死发展定义为肿瘤的引擎 多样化和攻击性，以及早期和转移阶段的临床背景 预防坏死可能有利于乳腺癌和肿瘤类型患者的环境。