Investigating mechanisms of chemoresistance in triple-negative breast cancer

项目摘要 化疗仍然是三阴性乳腺癌(TNBC)患者的标准护理， 影响20%的乳腺癌患者。然而，50%的局限性TNBC患者接受了 新辅助化疗显示治疗后残留癌症负担，高达25%的患者 接受这种治疗将在五年内发生转移复发。两者之间的不佳联系 化疗和患者结局强调了TNBC患者面临的两个主要问题：化疗耐药性， 当地环境中的肿瘤细胞受到保护，不会因化疗而死亡，以及 化疗诱导的转移，即化疗引起的肿瘤固有特性和 肿瘤微环境驱动肿瘤的侵袭，导致肿瘤复发。之前的研究已经证明 细胞迁移和细胞外基质(ECM)重构与化疗耐药的TNBC有关。目标是 这一建议的目的是了解ECM促进化疗耐药的机制和 化疗诱导的TNBC转移。 我们提供了在TNBC肿瘤中上调的个别蛋白驱动耐药性的初步数据 化疗药物紫杉醇和组织蛋白酶B(CTSB)表达 ECM蛋白分成小片段，防止化疗耐药性的发展。我们将剖析 CTSB及其降解的细胞外基质蛋白对紫杉醇的作用机制 以及这些片段是否可用于追踪和靶向体内的化疗耐药。我们还有 研究发现，化疗导致乳腺肿瘤细胞外基质成分发生变化。 具体地说，紫杉醇治疗导致IV型胶原蛋白含量增加，这是一种ECM蛋白， 促进肿瘤的侵袭和转移。我们的目标是确定分泌细胞外基质蛋白的细胞类型。 如化疗后的IV型胶原，确定这些ECM蛋白对 化疗诱导的转移，以及这些通路是否可以靶向阻止肿瘤的发展 复发的可能性。 在成功完成拟议的研究后，我们的贡献将是对 TNBC肿瘤中ECM蛋白上调如何参与化疗耐药及化疗的改变 ECM可促进复发和转移扩散。这些贡献将是重大的，因为 所有的TNBC患者都接受化疗，转移性复发是目前尚未满足的临床需求。结果 这些研究将为化疗耐药的机制提供新的概念性见解 化疗诱导的转移，并将使我们能够开发新的战略来跟踪、预测和克服 TNBC的化疗耐药。

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.