The role of entosis in human cancers

嵌入在人类癌症中的作用

基本信息

批准号：
9249491
负责人：
Michael H. Overholtzer
金额：
$ 39.73万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249491
关键词：
Actomyosin Alpha Cell Aneuploidy Autophagocytosis Breast Carcinoma Cell Adhesion Cell Death Cell Death Induction Cell Proliferation Cell Survival Cell-Cell Adhesion Cells Cellular Structures Colon Carcinoma Digestion Disease Progression Glucose Human Link Lipids Lysosomes Malignant Neoplasms Malignant neoplasm of pancreas Mechanics Mediating Membrane Metabolic stress Molecular Nature Nutrient Orthologous Gene Pancreatic carcinoma Pathway interactions Population Process Protein Family Proteins Regulation Role Signal Transduction Starvation Stress Supporting Cell Tumorigenicity Vacuole Withdrawal Work adenylate kinase cancer cell cell killing deprivation experimental study killings malignant breast neoplasm novel nutrient deprivation programs public health relevance rho GTP-Binding Proteins tumor tumor progression tumorigenesis tumorigenic uptake

项目摘要

DESCRIPTION (provided by applicant): Recently a novel cell death mechanism occurring in cancer was described called entosis, where cancer cells were found to engulf and kill their neighbors through a non-apoptotic mechanism involving autophagy proteins and lysosome-mediated cell digestion. We have found that entosis has tumor-suppressive activity, linked to the induction of cell death, but also the ability to promote tumor progression, as this process induces aneuploidy, and provides cancer cells with nutrients that can support cell survival and proliferation. We have shown that this dual nature combines to make entosis a form of cell competition, where `winner' cells within a cancer cell population engulf and kill neighboring `loser' cells, and benefit from the nutrients that they scavenge. Here we propose to investigate our recent finding that metabolic stress, in the form of glucose withdrawal, is a strong inducer of entosis in cancer cell populations. This program therefore acts, similar to other homeostatic mechanisms such as autophagy, to allow cells to respond to starvation stress by recovering essential nutrients. Under conditions of glucose starvation, winner cells ingest losers and benefit from the nutrients that they recover, suggesting that glucose starvation induces a novel form of cell competition in cancers that is predicted to contribute significantly to disease progression. This proposal describes plans to elucidate the signaling mechanisms that control starvation-induced entosis and its effects on cancer progression.

描述（由适用提供）：最近描述了一种新型的细胞死亡机制，称为ENSIS，在其中发现癌细胞通过涉及自噬蛋白和溶酶体介导的细胞消化的非凋亡机制吞噬并杀死其邻居。我们发现，ENSIS具有肿瘤抑制活性，与细胞死亡的诱导以及促进肿瘤进展的能力有关，因为这种过程诱导性诱导性非整倍性，并为癌细胞提供可以支持细胞存活和增殖的营养。我们已经表明，这种双重性质结合起来使ENSIS成为细胞竞争的形式，在癌细胞群体中的“赢家”细胞吞噬并杀死邻近的“失败者”细胞，并受益于它们清除的营养。在这里，我们建议调查最近的发现，即以葡萄糖戒断形式的代谢压力是强大的诱导剂癌细胞种群的诱惑。因此，该程序的作用类似于其他体内稳态机制，例如自噬，可以通过恢复必需的营养素来应对饥饿应激。在葡萄糖饥饿的条件下，赢家细胞摄入失败者并受益从它们所恢复的营养中，表明葡萄糖饥饿引起了癌症中一种新型的细胞竞争形式，预计会对疾病进展产生重大贡献。该提案描述了阐明控制饥饿引起的ENSIS及其对癌症进展的影响的计划机制的计划。