Investigating mechanisms of chemoresistance in triple-negative breast cancer

研究三阴性乳腺癌的化疗耐药机制

• 批准号: 10549343
• 负责人: Madeleine Julie Oudin
• 金额: $ 34.01万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-11 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549343
• 关键词: Adipocytes; Adjuvant Chemotherapy; Affect; Aftercare; Automobile Driving; Breast Cancer Cell; Breast Cancer Patient; Cancer Burden; Caspase; Cathepsins B; Cell secretion; Cessation of life; Chemoresistance; Clinical; Collagen; Collagen Type IV; Crosslinker; Data; Development; Drug resistance; Endothelial Cells; Environment; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Gene Expression Profile; Glycoproteins; Goals; Human; In Vitro; Individual; Invaded; Laminin; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Metastasis Induction; Metastatic/Recurrent; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Paclitaxel; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Population; Process; Property; Proteins; Proteoglycan; Recurrence; Relapse; Research; Residual Cancers; Resistance; Role; Sampling; Signal Transduction; Structural Protein; Structure; Testing; Therapeutic; Tissues; Tumor Tissue; Up-Regulation; cell motility; cell type; chemotherapy; improved; in vivo; insight; malignant breast neoplasm; neoplastic cell; novel; prevent; response; standard of care; therapy outcome; three-dimensional modeling; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Chemotherapy remains the standard of care for patients with triple-negative breast cancer (TNBC), which affects 20% of patients with breast cancer. However, 50% of patients with localized TNBC treated with neoadjuvant chemotherapy display residual cancer burden after treatment and up to 25% of patients who receive this treatment will suffer metastatic recurrence within five years. The poor association between chemotherapy and patient outcome emphasizes two major problems for TNBC patients: chemoresistance, where tumor cells within the local environment are protected and do not die in response to chemotherapy, and chemotherapy-induced metastasis, where chemotherapy-induced changes in tumor intrinsic properties and the tumor microenvironment drive invasion which leads to recurrence. Previous studies have demonstrated that cell migration and extracellular matrix (ECM) remodeling are associated with chemoresistant TNBC. The goal of this proposal is to understand the mechanisms by which the ECM contributes to chemoresistance and chemotherapy-induced metastasis in TNBC. We provide preliminary data that individual proteins upregulated in TNBC tumors drive resistance to chemotherapy drug Paclitaxel and that expression of Cathepsin B (CTSB), a protease which degrades these ECM proteins into small fragments, protects against the development of chemoresistance. We will dissect the mechanism by which the protease CTSB and the ECM proteins it degrades influence response to Paclitaxel in TNBC and whether these fragments can be used to track and target chemoresistance in vivo. We have also found that chemotherapy treatment leads to changes in the ECM composition of mammary tumors. Specifically, Paclitaxel treatment leads to an increased abundance of Collagen IV, an ECM protein which promote invasion and metastasis in TNBC. Our goal is to determine the cell types that secrete ECM proteins such as Collagen IV after chemotherapy treatment, determine the contribution of these ECM proteins to chemotherapy-induced metastasis, and whether these pathways can be targeted to prevent the development of recurrence. Upon successful completion of the proposed research, our contribution is expected to be an understanding of how ECM proteins upregulated in TNBC tumors contribute to chemoresistance and how chemotherapy alters the ECM to promote recurrence and metastatic dissemination. These contributions will be significant because all TNBC patients receive chemotherapy and metastatic recurrence is a current unmet clinical need. Results from these studies will provide novel conceptual insights on mechanisms of chemoresistance and chemotherapy-induced metastasis and will allow us to develop new strategies to track, predict and overcome chemoresistance in TNBC.

项目概要 化疗仍然是三阴性乳腺癌 (TNBC) 患者的标准治疗方法， 影响 20% 的乳腺癌患者。然而，50% 的局部 TNBC 患者接受了 新辅助化疗显示治疗后残留的癌症负担，高达 25% 的患者 接受这种治疗的人会在五年内出现转移性复发。之间的不良关联 化疗和患者结果强调了 TNBC 患者的两个主要问题：化疗耐药性、 局部环境中的肿瘤细胞受到保护，不会因化疗而死亡，并且 化疗引起的转移，其中化疗引起肿瘤内在特性的变化和 肿瘤微环境驱动侵袭，导致复发。先前的研究表明 细胞迁移和细胞外基质 (ECM) 重塑与化疗耐药的 TNBC 相关。目标 该提案的目的是了解 ECM 促进化疗耐药的机制和 TNBC 化疗引起的转移。 我们提供的初步数据表明，TNBC 肿瘤中个别蛋白上调可驱动耐药性 化疗药物紫杉醇和组织蛋白酶 B (CTSB) 的表达，这是一种降解这些物质的蛋白酶 将 ECM 蛋白分解成小片段，防止化学耐药性的发展。我们将剖析 蛋白酶 CTSB 及其降解的 ECM 蛋白影响紫杉醇反应的机制 TNBC 以及这些片段是否可用于跟踪和靶向体内化疗耐药性。我们还有 发现化疗导致乳腺肿瘤的 ECM 成分发生变化。 具体来说，紫杉醇治疗会导致 IV 型胶原蛋白丰度增加，这是一种 ECM 蛋白， 促进TNBC的侵袭和转移。我们的目标是确定分泌 ECM 蛋白的细胞类型 例如化疗后的 IV 型胶原蛋白，确定这些 ECM 蛋白对 化疗引起的转移，以及是否可以针对这些途径来预防其发展 的复发。 成功完成拟议的研究后，我们的贡献预计将是了解 TNBC 肿瘤中 ECM 蛋白上调如何导致化疗耐药以及化疗如何改变 ECM促进复发和转移扩散。这些贡献将是巨大的，因为 所有 TNBC 患者均接受化疗，而转移复发是当前未满足的临床需求。结果 这些研究将为化疗耐药机制提供新颖的概念见解 化疗引起的转移，将使我们能够开发新的策略来跟踪、预测和克服 TNBC 中的化学耐药性。