Role of Autophagy in Cancer

描述(申请人提供)：细胞通过宏观自噬(以下简称自噬)过程捕获细胞内的蛋白质和细胞器，将它们运送到溶酶体，在那里它们被降解。自噬货物的分解产物，如氨基酸、糖、核苷和脂类，从溶酶体释放到细胞质中，在那里它们被重复使用。自噬因此回收细胞内的成分，以维持细胞和有机体的新陈代谢，并在饥饿中存活，这一功能从酵母到哺乳动物都是保守的。自噬也是清除细胞废物的一种机制，如受损的蛋白质和细胞器，特别是线粒体，积累的这些废物是有毒的。自噬的这种蛋白质和细胞器质量控制功能也是高度保守的，是动态平衡所必需的。自噬水平通常很低，但饥饿和压力会极大地诱导自噬，以促进细胞适应。癌细胞也依赖于自噬，但比正常细胞更依赖自噬。这可能是由于癌细胞在紧张的微环境中生长和停留所产生的高代谢需求所致。与正常细胞不同，癌细胞通常在饲料条件下诱导自噬。例如，RAS驱动的癌症通常具有高水平的基础自噬，并且极其依赖自噬来维持线粒体呼吸、在压力中生存和肿瘤形成。因此，与正常细胞相比，一些癌症可能对自噬上瘾，并对自噬抑制更敏感，这促使人们对抑制自噬以改进癌症治疗感兴趣。自噬究竟如何支持癌症的生长和生存，正常组织和肿瘤受到多大程度的不同影响，以及最有效的手段是在临床上实施这一概念，仍然是悬而未决的问题。为了解决这些问题，我们使用基因工程小鼠模型(GEMM)研究了K-RasG12D驱动的非小细胞肺癌(NSCLC)和B-rafV600E驱动的肺癌中自噬的作用。我们发现，必要的自噬基因ATG7的缺失会导致肿瘤细胞积累大量有缺陷的线粒体并经历萎缩。ATG7缺乏也会使肺腺瘤和癌的进展转向嗜酸细胞瘤。嗜酸细胞瘤是一种罕见的、以良性为主的肿瘤，发生在上皮组织中，其特征是大量积累有呼吸障碍的突变线粒体。这一发现首次揭示了自噬是癌症命运的决定因素，自噬缺陷可能是嗜酸细胞瘤发生的分子基础，当自噬受损时，嗜酸细胞瘤可以起源于腺瘤和癌。我们将检验中心假设，即自噬缺陷是嗜酸细胞瘤发生的分子基础。我们将确定ATG7缺陷是否会导致线粒体基因组突变，从而将癌症转化为嗜酸细胞瘤，基本自噬基因的突变是否会导致人类嗜酸细胞瘤，以及通过敲除自噬而产生的嗜酸细胞瘤是否会对代谢应激产生敏感性，从而加强癌症治疗。

DESCRIPTION (provided by applicant): Cells capture intracellular proteins and organelles by the process of macroautophagy (autophagy hereafter), which delivers them to lysosomes where they are degraded. The breakdown products of autophagy cargo such as amino acids, sugars, nucleosides and lipids, are released from lysosomes into the cytoplasm where they are reused. Autophagy thereby recycles intracellular components to sustain cell and organism metabolism and survival in starvation, a function conserved from yeast to mammals. Autophagy is also a mechanism for eliminating cellular waste such as damaged proteins and organelles, particularly mitochondria, the accumulation of which is toxic. This protein and organelle quality control function of autophagy is also highly conserved and required for homeostasis. Autophagy levels are normally low, but are dramatically induced by starvation and stress to facilitate cellular adaptation. Cancer cells also rely on autophagy, but more so than normal cells. This may be due to high metabolic demand imposed by cancer cell growth and residence in a stressful microenvironment. In contrast to normal cells, cancer cells often have autophagy induced under fed conditions. For example, Ras-driven cancers commonly have high levels of basal autophagy and are extremely dependent on autophagy for sustaining mitochondrial respiration, for survival in stress and for tumorigenesis. Thus, in comparison to normal cells, some cancers may be addicted to autophagy and preferentially sensitive to autophagy inhibition, prompting interest in inhibiting autophagy to improve cancer therapy. Precisely how autophagy supports cancer growth and survival, the extent to which normal tissues and tumors are differentially affected, and the most effective means is to implement this concept in the clinic, remain open questions. To address these questions we examined the role of autophagy using genetically engineered mouse models (GEMMs) for K-rasG12D-driven non-small-cell lung cancer (NSCLC) and B-rafV600E- driven lung cancer. We found that deficiency in the essential autophagy gene atg7 causes tumor cells to accumulate large numbers of defective mitochondria and undergo atrophy. Atg7 deficiency also diverts progression of lung adenomas and carcinomas to oncocytomas. Oncocytomas are rare, predominantly benign neoplasms that arise in epithelial tissues that are characterized by the accumulation of large numbers of respiration-defective, mutant mitochondria. This discovery revealed for the first time that autophagy is a cancer fate determinant, that autophagy defects may be the molecular basis for the genesis of oncocytomas, and that oncocytomas can derive from adenomas and carcinomas when autophagy is impaired. We will test the central hypothesis that autophagy defects are the molecular basis for the genesis of oncocytomas. We will determine if atg7 deficiency produces mitochondrial genome mutations that convert carcinomas to oncocytomas, if mutations in essential autophagy genes cause human oncocytomas, and if producing oncocytomas by knocking out autophagy creates sensitivity to metabolic stress, enhancing cancer therapy.