THE EFFECT OF TUMOR MICROENVIRONMENT ON METASTASIS

肿瘤微环境对转移的影响

• 批准号: 10097181
• 负责人: JOHN S CONDEELIS
• 金额: $ 50.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10097181
• 关键词: Actins; Address; Anatomy; Biosensor; Blood Circulation; Blood Vessels; Blood capillaries; Cells; Chemoresistance; Data; Diagnosis; Disease; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Endothelial Cells; Event; Excision; Extravasation; Future; Immunofluorescence Immunologic; Kinetics; Life; Light; Lung; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastasis Induction; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Metastatic to; Modeling; Molecular; Molecular Target; NF-kappa B; Neoplasm Metastasis; Organ; Patient-Focused Outcomes; Patients; Phenotype; Population; Primary Neoplasm; Process; Protein Isoforms; Publishing; Resolution; STEM program; Savings; Signal Transduction; Site; Techniques; Time; Tissues; Tumor Biology; Tumor-associated macrophages; Woman; cancer cell; carcinogenesis; chemotherapy; curative treatments; density; genetic regulatory protein; improved outcome; in vivo; in vivo imaging; insight; lung cancer cell; macrophage; malignant breast neoplasm; mortality; neoplastic cell; new technology; notch protein; novel; novel strategies; programs; stem; stem cells; stemness; transcription factor; tumor; tumor growth; tumor microenvironment

ABSTRACT Metastasis, the primary cause of breast cancer-related mortality, is a multistep process culminating with the formation of tumor foci within distant organs. However, only a subpopulation of cancer cells within the primary tumor microenvironment is capable of completing the entire metastatic cascade, which includes intravasation, survival in circulation, extravasation, and tumor growth at distant sites. Currently, there are no curative treatments for metastatic breast cancer. Understanding the factors that induce a pro-metastatic cancer cell phenotype and cancer cell dissemination mechanisms is key to developing life-saving therapies against this deadly disease. We identified a population of highly invasive, non-proliferating, non-apoptotic, chemo-resistant cancer cells capable of intravasation. These cells express high levels of MenaINV, a pro-metastatic isoform of the actin-regulatory protein Mena, and low levels of the anti-metastatic isoform, Mena11a. We found that MenaINV expression (published) and a stem cell program (preliminary results) are induced by Notch signaling in tumor cells by direct contact with tumor-associated macrophages. The emergence of MenaINV-High/Mena11aLow stem cells may be one of the crucial steps to metastasis because these cells are not only intravasation- competent but also have tumor-initiating capability. In primary breast tumors, cancer cells expressing MenaINV- High/Mena11aLow are able to enter blood vessels through Tumor Microenvironments of Metastasis (TMEM) doorways. These tightly controlled transient openings in capillary walls were first described by our group and are composed of macrophages, endothelial cells and Mena-expressing tumor cells in direct physical contact. Similar micro-anatomical structures are also observed in lung metastases, but the dissemination mechanism from this secondary site is currently unknown. Interestingly, we found that chemotherapy induces co- expression of MenaINV and stem cell transcription factor Sox9 in tumor cells through a macrophage-dependent mechanism. Importantly, we and others found that chemotherapy also increases the density of TMEM doorways. Thus, we hypothesize that tumor-associated macrophages induce a pro-metastatic cancer cell phenotype in primary tumors and metastatic foci, enabling them to disseminate via TMEM doorways, and that this process is potentiated by chemotherapy. We aim to delineate the involvement of NF-kB and Notch in co- induction of invasive (MenaINV-High) and stem phenotypes in both primary tumor and lung metastases in vivo, evaluate cancer cell dissemination mechanisms in lung metastases and evaluate the effect of chemotherapy on cancer cell re-dissemination from lung metastasis and co-activation of stem and MenaINV-High phenotype. Our findings will provide mechanistic insights into the effects of the tumor microenvironment on the induction of metastasis and cancer cell re-dissemination from metastatic foci. This will enable us to identify molecular targets for future therapies that could be combined with chemotherapy to improve outcomes for patients with metastatic disease which would be a major advance in the battle against breast cancer.

抽象的 转移是与乳腺癌相关死亡率的主要原因，是一个多步过程 远处器官内肿瘤焦点的形成。但是，仅在原发性癌细胞中进行亚群 肿瘤微环境能够完成整个转移性级联反应，包括侵入， 在遥远部位的循环，渗出和肿瘤生长中的生存。目前，没有治愈性 转移性乳腺癌的治疗方法。了解诱导促旋转癌细胞的因素 表型和癌细胞传播机制是开发挽救生命的疗法的关键 致命疾病。我们确定了高度侵入性，非增殖，非凋亡，耐化学性的人群 癌细胞能够插入。这些细胞表达高水平的Menainv，这是一种促成的亚替代同种型 肌动蛋白调节蛋白MENA和低水平的抗中性同工型MENA11A。我们发现 MENAINV表达（已发布）和干细胞程序（初步结果）是通过Notch信号传导诱导的 肿瘤细胞通过直接接触肿瘤相关的巨噬细胞。 Menainv-High/Mena11Alow的出现 干细胞可能是转移的关键步骤之一，因为这些细胞不仅是侵入性的 - 胜任，但也具有肿瘤发射能力。在原发性乳腺肿瘤中，表达Menainv-的癌细胞 高/MENA11ALOW能够通过转移的肿瘤微环境进入血管（TMEM） 门口。这些毛细管墙中这些紧密控制的瞬态开口首先由我们的小组描述 由巨噬细胞，内皮细胞和表达男性肿瘤细胞的直接接触组成。 在肺部转移中也观察到了相似的微型解剖结构，但是传播机制 目前未知从这个辅助站点开始。有趣的是，我们发现化疗引起了共同 通过巨噬细胞依赖性的肿瘤细胞中MENAINV和干细胞转录因子SOX9的表达 机制。重要的是，我们和其他人发现化疗也增加了TMEM的密度 门口。因此，我们假设肿瘤相关的巨噬细胞会诱导促癌症细胞 原发性肿瘤和转移灶中的表型，使它们能够通过TMEM门口传播，并且 这个过程是通过化学疗法增强的。我们的目的是描述NF-KB和Notch参与共同 在体内原发性肿瘤和肺转移中诱导浸润性（MENAINV-HIGH）和茎表型， 评估肺转移酶中癌细胞的传播机制，并评估化学疗法的作用 关于肺转移的癌细胞再隔离以及茎和Menainv-High表型的共激活。 我们的发现将提供有关肿瘤微环境对诱导的影响的机械见解 转移灶的转移和癌细胞再启用。这将使我们能够识别分子 未来疗法的靶标可以与化学疗法结合使用，以改善患者的预后 转移性疾病将是与乳腺癌作斗争的重大进步。