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.

项目概要 我们仍然无法开发出预防播散性乳腺肿瘤出现的选择性疗法 细胞致命性转移需要新的方法。我们已经证明，播散性肿瘤细胞 （DTC）占据血管周围生态位（PVN），该生态位促进化疗耐药性，并且 靶向 DTC 和 PVN 之间的相互作用使 DTC 对化疗敏感。翻译一下这个 乳腺癌临床前模型的方法可预防 60% 以上的高危小鼠发生转移。 对其余小鼠的抵抗机制的质疑使我们考虑动态反应 化疗的血管生态位。我们的初步数据表明，基因毒性剂会引发 促生存因子分泌到 PVN 中，并且是这种化疗相关的主要触发因素 血管分泌组是DNA损伤反应（DDR）。因此，我们的目标是针对原因（即 DDR）和血管进化的结果（即化疗相关的血管分泌组）， 我们怀疑这会促进 DTC 的治疗耐药性。我们将通过两个具体目标来实现这一目标： 具体目标 1. 确定单个细胞外因子是否由血管内皮引起 化疗可以保护 DTC。我们已经定义了对 DNA 损伤剂的整体血管反应。 Netrin-1 是该分泌蛋白组的一个重要组成部分，具有已记录的促生存功能。我们的数据表明，内 细胞来源的 Netrin-1 可以保护 DTC 免受化疗的影响。使用器官型、转基因和临床前模型 其他，我们将确定：i) 内皮细胞是否是化疗引起的 Netrin-1 的相关来源 体内； ii) 以 Netrin-1 作为佐剂是否会使 DTC 对化疗敏感； iii) 该协同器是否 针对PVN中预先存在的保护因素进行gizes； iv) 这些方法的安全性。 具体目标 2. 确定血管内皮中 DNA 损伤驱动的信号通路，从而诱导 化疗相关的血管分泌蛋白组。我们的初步数据表明，基因毒性疗法会引起 来自静止内皮细胞的刻板 DDR，并且针对该反应的成核剂可抑制 ma- 大部分化疗相关的血管分泌蛋白组。这种方法可能是一个更稳健的替代方案 针对单一的促生存因子，例如 Netrin-1。在这里，我们将识别并靶向信号通路 将 DDR 连接到血管分泌蛋白组，并测量该方法的功效和毒性。 这项工作的意义和创新在于化学保护作用的起源和输出的发现。 DTC 利基中的因素。针对这两个目标将导致第一种方法专门针对 DTC，从而影响 乳腺癌以积极且持久的方式存活。