Chemotherapy-driven evolution of the vascular secretome and its role in therapeutic resistance

化疗驱动的血管分泌组进化及其在治疗抵抗中的作用

• 批准号: 10321289
• 负责人: Cyrus M Ghajar
• 金额: $ 12.08万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321289
• 关键词: Adjuvant; Affect; Animals; Benchmarking; Blood Vessels; Bone Marrow; Bone Tissue; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast cancer metastasis; Cell Cycle; Cell Survival; Cell Therapy; Cells; Chemoprotective Agent; DNA Damage; Data; Distant; Endothelial Cells; Endothelium; Estrogen receptor positive; Evolution; Future; Goals; Individual; Integrins; Left; Ligands; Liver; Lung; Measures; Mediating; Metastatic Neoplasm to the Bone; Modeling; Mus; Mutagens; NTN1 gene; Neoplasm Metastasis; Output; Patients; Phase; Plant Roots; Pre-Clinical Model; Primary Neoplasm; Protein Array; Recurrence; Regimen; Resistance; Risk; Role; Safety; Signal Pathway; Signal Transduction; Site; Source; Stress; Testing; Tissues; Toxic effect; Transgenic Model; Translating; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; Vertebral column; Work; breast cancer survival; chemotherapy; extracellular; genotoxicity; hormone therapy; improved; in vivo; innovation; knock-down; malignant breast neoplasm; metastasis prevention; neoplastic cell; novel; novel strategies; pre-clinical; prevent; protective factors; response; sensor; stem; targeted treatment; therapy resistant; vascular factor; von Willebrand Factor

PROJECT SUMMARY Our continued inability to develop selective therapies that prevent the emergence of disseminated breast tumor cells into lethal metastases necessitates new approaches. We have shown that disseminated tumor cells (DTCs) occupy the perivascular niche (PVN), that this niche promotes chemotherapeutic resistance, and that targeting interactions between DTCs and the PVN sensitizes DTCs to chemotherapy. Translating this approach to pre-clinical models of breast cancer prevented metastases in over 60% of at-risk mice. Questioning the mechanism(s) of resistance in the remainder of mice led us to consider the dynamic response of the vascular niche to chemotherapy. Our preliminary data indicate that genotoxic agents trigger the secretion of pro-survival factors into the PVN, and that the major trigger of this chemotherapy-associated vascular secretome is the DNA damage response (DDR). Therefore, here our goal is to target the cause (i.e., the DDR) and the consequence (i.e., the chemotherapy-associated vascular secretome) of vascular evolution, which we suspect promotes therapeutic resistance of DTCs. We will pursue this goal through 2 specific aims: Specific Aim 1. To determine whether individual extracellular factors elicited from vascular endothelium by chemotherapy protect DTCs. We have defined a global vascular response to DNA damaging agents. Netrin-1 is a prominent component of this secretome with documented pro-survival functions. Our data show that endo- thelial-derived Netrin-1 protects DTCs from chemotherapy. Using organotypic, transgenic and preclinical mod- els, we will determine: i) whether endothelial cells are the relevant source of chemotherapy-elicited Netrin-1 in vivo; ii) whether targeting Netrin-1 as an adjuvant sensitizes DTCs to chemotherapy; iii) whether this syner- gizes with targeting pre-existing protective factors in the PVN; and iv) the safety of these approaches. Specific Aim 2. To identify DNA damage driven signaling pathways in vascular endothelium that induce the chemotherapy-associated vascular secretome. Our preliminary data demonstrate that genotoxic therapy elicits a stereotypic DDR from quiescent endothelium, and that targeting a nucleator of this response mutes the ma- jority of the chemotherapy-associated vascular secretome. This approach may be a more robust alternative to targeting a single pro-survival factor such as Netrin-1. Here, we will identify and target the signaling pathway that connects DDR to the vascular secretome, and measure the efficacy and toxicity of this approach. The significance and innovation of this work lie in the discovery of origins and outputs of chemoprotective factors in the DTC niche. Targeting both will result in the first approach to specifically target DTCs, impacting breast cancer survival in a positive and lasting fashion.

项目摘要 我们持续无法开发选择性疗法，以防止散布乳腺肿瘤的出现 细胞进入致命转移需要新方法。我们已经表明散布肿瘤细胞 （DTC）占据了血管周围壁ne（PVN），该利基市场促进了化学治疗性，并且 DTC和PVN之间的相互作用将DTC敏感到化学疗法。翻译这个 乳腺癌临床前模型的方法可预防60％的高危小鼠转移。 质疑其余小鼠的抗药性机制，使我们考虑了动态反应 化学疗法的血管生态位。我们的初步数据表明，遗传毒性剂触发 促生存因子分泌到PVN中，并且该化学疗法相关的主要触发因素 血管分泌组是DNA损伤反应（DDR）。因此，在这里我们的目标是针对原因（即 DDR）和血管进化的后果（即，与化学疗法相关的血管分泌组）， 我们怀疑这会促进DTC的治疗性。我们将通过2个特定目标来追求这一目标： 具体目的1。确定是否通过 化学疗法保护DTC。我们已经定义了对DNA破坏药物的全球血管反应。 Netrin-1 是该分泌组成的重要组成部分，并具有记录的生存功能。我们的数据表明，endo- Thelial衍生的Netrin-1可保护DTC免受化学疗法。使用器官，转基因和临床前模型 Els，我们将确定：i）内皮细胞是否是化学疗法引起的Netrin-1的相关来源 体内ii）靶向Netrin-1作为佐剂是否会使DTC对化学疗法敏感； iii）是否这种协同作用 - PVN中针对预先存在的保护因子的盖牌； iv）这些方法的安全。 具体目的2。鉴定DNA损伤驱动的信号通路在血管内皮中诱导诱导 化学疗法相关的血管分泌组。我们的初步数据表明，遗传毒性疗法引起 静态内皮的刻板印象DDR，靶向该反应的成核器使MA- 化学疗法相关的血管分泌组的变体。这种方法可能是更强大的选择 靶向单个促寿使因子，例如Netrin-1。在这里，我们将识别并定位信号通路 这将DDR连接到血管分泌组，并测量这种方法的功效和毒性。 这项工作的重要性和创新在于发现化学保护的起源和产出 DTC利基市场中的因素。针对两者都将导致第一种专门针对DTC的方法，从而影响 乳腺癌以积极而持久的方式生存。