THE EFFECT OF TUMOR MICROENVIRONMENT ON METASTASIS

肿瘤微环境对转移的影响

• 批准号: 10652273
• 负责人: JOHN S CONDEELIS
• 金额: $ 49.52万
• 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/10652273
• 关键词: Actins; Anatomy; Biosensor; Blood Vessels; Blood capillaries; Cells; Chemoresistance; Circulation; Data; Diagnosis; Disease; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Endothelial Cells; Event; Excision; Extravasation; Future; Immunofluorescence Immunologic; Kinetics; Life; Light; Lung; Macrophage; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastasis Induction; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Microanatomy; Modeling; Molecular; Molecular Target; NF-kappa B; Neoplasm Metastasis; Organ; Patient-Focused Outcomes; Patients; Phenotype; Population; Primary Neoplasm; Process; Protein Isoforms; Publishing; Resolution; 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; malignant breast neoplasm; mortality; neoplastic cell; new technology; notch protein; novel; novel therapeutic intervention; programs; stem; stem cells; stemness; transcription factor; tumor; tumor growth; tumor initiation; 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 转移是乳腺癌相关死亡的主要原因，是一个多步骤的过程，最终以 远处器官内肿瘤灶的形成。然而，只有原发细胞内的癌细胞亚群 肿瘤微环境能够完成整个转移级联反应，包括内渗、 循环中的存活、外渗和远处肿瘤的生长。目前尚无特效药 转移性乳腺癌的治疗。了解诱导促转移癌细胞的因素 表型和癌细胞传播机制是开发针对这种情况的挽救生命疗法的关键 致命的疾病。我们确定了一个具有高度侵袭性、非增殖性、非凋亡性、化疗耐药性的群体 癌细胞能够内渗。这些细胞表达高水平的 MenaINV，这是一种促转移亚型 肌动蛋白调节蛋白 Mena 和低水平的抗转移亚型 Mena11a。我们发现 MenaINV 表达（已发表）和干细胞程序（初步结果）由 Notch 信号传导诱导 肿瘤细胞通过与肿瘤相关巨噬细胞直接接触。 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内渗- 有能力但也有肿瘤启动能力。在原发性乳腺肿瘤中，癌细胞表达 MenaINV- High/Mena11aLow 能够通过肿瘤转移微环境 (TMEM) 进入血管 门口。我们的小组首先描述了毛细血管壁中这些严格控制的瞬时开口，并且 由直接物理接触的巨噬细胞、内皮细胞和表达 Mena 的肿瘤细胞组成。 在肺转移瘤中也观察到类似的微观解剖结构，但传播机制 目前尚不清楚来自该辅助站点的信息。有趣的是，我们发现化疗会诱导 MenaINV 和干细胞转录因子 Sox9 在肿瘤细胞中通过巨噬细胞依赖性表达 机制。重要的是，我们和其他人发现化疗也会增加 TMEM 的密度 门口。因此，我们假设肿瘤相关巨噬细胞诱导促转移癌细胞 原发性肿瘤和转移灶的表型，使它们能够通过 TMEM 门口传播，并且 化疗可增强这一过程。我们的目标是描述 NF-kB 和 Notch 在共同作用中的参与 在体内原发肿瘤和肺转移中诱导侵袭性（MenaINV-High）和干表型， 评估肺转移癌细胞的播散机制并评估化疗效果 癌细胞从肺转移中重新传播以及干细胞和 MenaINV-High 表型的共同激活。 我们的研究结果将为肿瘤微环境对诱导的影响提供机制见解。 转移和癌细胞从转移灶重新传播。这将使我们能够识别分子 未来治疗的目标可以与化疗相结合，以改善患有癌症的患者的预后 转移性疾病，这将是对抗乳腺癌的重大进展。