Autophagy in Tumor Progression and Metastasis

描述（由申请人提供）：多年前“成功”治疗的乳腺癌患者出现复发和/或转移性疾病，这突出了理解肿瘤细胞侵袭、扩散和外周休眠作为导致显性转移生长的因素的基础的重要性。这一提议的首要假设是，一个被称为自噬的过程促进了转移性乳腺癌的一些最具侵略性和最棘手的特征，即增加肿瘤细胞扩散，增加肿瘤细胞休眠，可导致疾病复发，自噬促进“干细胞状态”，这反过来又与耐药性有关。通过基因

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.