Autophagy in Tumor Progression and Metastasis

描述(由申请人提供)：了解肿瘤细胞在外围侵袭、扩散和休眠的基础是导致明显转移的因素的重要性，在多年前“成功”治疗的乳腺癌患者中复发和/或转移疾病的出现凸显了这一点。这一提议的主要假设是，自噬过程促进了转移性乳腺癌的一些最具侵袭性和最难处理的特征，即肿瘤细胞扩散增加，肿瘤细胞休眠增加，可能导致疾病复发，自噬促进了“干细胞状态”，这反过来又与耐药性有关。由基因决定的 通过化学调控细胞诱导自噬的能力，我们将首次研究是否可以利用侵袭细胞对自噬的依赖来将它们从体内消除，从而有效地防止癌症的复发或转移。自噬是一种对营养缺乏和/或缺氧做出反应而激活的分解代谢过程，与细胞周期停滞、生长减少、细胞成分周转以及细胞存活有关。有三个新的概念正在被提出和测试：(1)自噬在肿瘤发生中扮演不同的角色，取决于它是在过程的早期起作用，在过程中可能起到抑制肿瘤发展的作用，还是在过程的后期起作用，我们认为它起到促进侵袭和转移的作用。(目标1)；(2)自噬通过促进焦点黏附复合体的周转而促进肿瘤细胞的迁移，而Ulk-1/FIP200复合体起着激活自噬和抑制焦点黏附周转的双重作用，这解释了自噬和细胞迁移是如何协调的(目标2)；(3)自噬是维持被称为“干细胞性”的肿瘤细胞的特性所必需的(目标2)。这些特性包括在体内连续移植时重新种植肿瘤的能力，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。这项拟议的工作对于提出一套新的假说来解释自噬在乳腺癌转移中的作用具有重要意义，虽然该提议的每个目标本身都是不同的，但通过确定肿瘤细胞迁移、侵袭、休眠和肿瘤增殖细胞的干细胞性质依赖于自噬的程度，我们将在理解晚期乳腺癌的这些不同特征如何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理解如何最好地防止肿瘤细胞扩散，预计这将减少转移，限制疾病复发，并提高乳腺癌患者的存活率。总而言之，该项目将涉及几个非常重要科学问题 提出问题，为乳腺癌转移的临床相关问题带来新的视角。

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.