Autophagy in Tumor Progression and Metastasis

自噬在肿瘤进展和转移中的作用

• 批准号: 8311298
• 负责人: KAY F MACLEOD
• 金额: $ 32.32万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-13 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311298
• 关键词: Actins; Address; Affect; Autophagocytosis; Blood Circulation; Brain; CD44 gene; CDKN2A gene; Cancer Patient; Catabolic Process; Cell Cycle Arrest; Cell Survival; Cells; Characteristics; Chloroquine; Clinical; Collagen; Complex; Dependence; Development; Disease; Disease Progression; Distant; Drug resistance; Exposure to; Fatty acid glycerol esters; Focal Adhesions; Genome Stability; Goals; Growth; Human; Hypoxia; Implant; In Vitro; Incidence; Lead; Link; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Metastatic Neoplasm to the Bone; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; NOD/SCID mouse; Nature; Neoplasm Metastasis; Nutrient; Organ; Organelles; Palpable; Pharmaceutical Preparations; Phenotype; Play; Primary Neoplasm; Process; Property; Recurrence; Role; Secondary to; Seeds; Site; Solid Neoplasm; Sorting - Cell Movement; Staging; Stem cells; Stress; Stress Fibers; Survival Rate; System; Testing; Time; Tissue Microarray; Transgenic Organisms; Transplantation; Tumor Cell Invasion; Tumor Stem Cells; Woman; Work; Xenograft procedure; aldehyde dehydrogenase 1; base; cancer recurrence; cancer stem cell; cell motility; chemotherapy; clinically relevant; deprivation; epithelial to mesenchymal transition; exposed human population; improved; in vivo; inhibition of autophagy; malignant breast neoplasm; migration; mortality; mouse model; neoplastic cell; novel; prevent; protein aggregate; response; self-renewal; stem; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The importance of understanding the basis of tumor cell invasiveness, dissemination and dormancy in the periphery as factors leading to the outgrowth of overt metastases is highlighted by the emergence of recurrent and/or metastatic disease in breast cancer patients that were "successfully" treated years before. The overarching hypothesis of this proposal is that a process known as autophagy promotes some of the most aggressive and intractable features of metastatic breast cancer, namely increased tumor cell dissemination, increased tumor cell dormancy that can lead to disease recurrence and that autophagy promotes the "stem cell state", that is in turn linked to drug resistance. By genetically and chemically modulating the ability of the cell to induce autophagy, we will examine for the first time whether we can exploit the dependence of invasive cells on autophagy to eliminate them from the body and thereby prevent cancer from recurring or metastasizing effectively. Autophagy is a catabolic process activated in response to nutrient deprivation and/or hypoxia and is associated with cell cycle arrest, reduced growth, turnover of cellular constituents but also cell survival. There are three new concepts that are being proposed and tested: (1) autophagy plays differing roles in tumorigenesis depending on whether it is acting early in the process, where it likely acts to suppress tumor development, or late in the process, where we propose it acts to promote progression to invasiveness and metastasis. (Aim 1); (2) autophagy is required for tumor cell migration by promoting focal adhesion complex turnover and that the Ulk-1/FIP200 complex plays a dual role activating autophagy and inhibiting focal adhesion turnover that explains how autophagy and cell migration are coordinated (Aim 2); (3) autophagy is required for maintaining characteristics of tumor cells that are known as "stem-like". These properties include the ability to re-seed tumors when serially transplanted in vivo, to self-renew under such conditions and to give rise to "differentiated" tumor cells that lack such stem cell lik properties (Aim 3). We will also examine how autophagy promotes drug resistance of tumor cells. The proposed work is significant in putting forward a novel set of hypotheses to explain the role of autophagy in breast cancer metastasis and while each aim of the proposal is distinct in its own right, there is the possibility that by determining the extent to which tumor cell migration, invasiveness, dormancy and the stem cell nature of tumor propagating cells are dependent on autophagy, that we will make a major advance in understanding how these different features of advanced breast cancer are linked. Hence, it is predicted that our work will contribute to our understanding of how best to prevent tumor cell dissemination that is predicted to lead to reduced metastasis, limit disease recurrence and improved survival rates amongst breast cancer patients. In summary, this project will address several highly significant scientific questions and bring new perspective to the clinically relevant problem of breast cancer metastasis. PUBLIC HEALTH RELEVANCE: The importance of understanding the mechanistic basis of how tumor cells escape the primary tumor and spread to distant organs where they survive in a dormant or stem-like state before growing out to form overt metastases is highlighted by the emergence of recurrent and/or metastatic disease in breast cancer patients that were treated for their primary cancer years earlier. We will test the role of autophagy, an adaptive response to nutrient deprivation, in breast cancer metastasis with the goal of providing a novel understanding of the factors that determine how and when tumor cells become invasive, disseminate, remain dormant or grow out as overt metastases.

描述（由申请人提供）：乳腺癌患者中复发和/或转移性疾病的出现凸显了了解肿瘤细胞侵袭性、传播和外周休眠的基础作为导致明显转移生长的因素的重要性。几年前就被“成功”治疗过。该提议的总体假设是，一种称为自噬的过程促进了转移性乳腺癌的一些最具侵袭性和棘手的特征，即增加的肿瘤细胞扩散、增加的肿瘤细胞休眠，这可能导致疾病复发，并且自噬促进“干细胞”的形成。细胞状态”，这又与耐药性相关。通过基因 通过化学调节细胞诱导自噬的能力，我们将首次研究是否可以利用侵袭性细胞对自噬的依赖性将其从体内消除，从而有效防止癌症复发或转移。自噬是响应营养缺乏和/或缺氧而激活的分解代谢过程，与细胞周期停滞、生长减少、细胞成分更新以及细胞存活相关。正在提出和测试三个新概念：（1）自噬在肿瘤发生中发挥不同的作用，具体取决于它是在过程的早期发挥作用（可能抑制肿瘤发展），还是在过程的后期发挥作用（我们建议）它的作用是促进侵袭和转移的进展。 （目标 1）； (2) 自噬是肿瘤细胞迁移所必需的，通过促进粘着斑复合物周转，而 Ulk-1/FIP200 复合物发挥激活自噬和抑制粘着斑周转的双重作用，这解释了自噬和细胞迁移是如何协调的（目标 2）； (3)自噬对于维持肿瘤细胞被称为“干细胞样”的特征是必需的。这些特性包括在体内连续移植时重新播种肿瘤的能力、在这种条件下自我更新的能力以及产生缺乏这种干细胞样特性的“分化”肿瘤细胞的能力（目标3）。我们还将研究自噬如何促进肿瘤细胞的耐药性。拟议的工作对于提出一套新的假设来解释自噬在乳腺癌转移中的作用具有重要意义，虽然该提案的每个目标本身都是不同的，但有可能通过确定肿瘤细胞自噬的程度肿瘤增殖细胞的迁移、侵袭、休眠和干细胞性质都依赖于自噬，因此我们将在理解晚期乳腺癌的这些不同特征之间的联系方面取得重大进展。因此，预计我们的工作将有助于我们了解如何最好地预防肿瘤细胞传播，从而减少乳腺癌患者的转移、限制疾病复发并提高生存率。总之，该项目将解决几个非常重要的科学问题 问题并为乳腺癌转移的临床相关问题带来新的视角。 公共健康相关性：了解肿瘤细胞如何逃离原发肿瘤并扩散到远处器官的机制基础的重要性，在远处器官中它们在生长形成明显转移之前以休眠或干状状态生存，这一点通过复发性和复发性肿瘤的出现凸显出来。 /或多年前接受原发性癌症治疗的乳腺癌患者的转移性疾病。我们将测试自噬（一种对营养剥夺的适应性反应）在乳腺癌转移中的作用，目的是对决定肿瘤细胞如何以及何时变得侵袭、传播、保持休眠或长出明显转移的因素提供新的理解。