The role of entosis in human cancers

 描述（由申请人提供）：最近描述了一种发生在癌症中的新的细胞死亡机制，称为内吞，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它们的邻居。我们已经发现，内吞具有肿瘤抑制活性，与诱导细胞死亡有关，但也具有促进肿瘤进展的能力，因为该过程诱导非整倍体，并为癌细胞提供可以支持细胞存活和增殖的营养物质。我们已经证明，这种双重性质结合起来，使entosis成为一种细胞竞争形式，其中癌细胞群中的“赢家”细胞吞噬并杀死邻近的“输家”细胞，并从它们吸收的营养中受益。在这里，我们建议调查我们最近的发现，即代谢应激，以葡萄糖戒断的形式，是一个强大的诱导剂， 在癌细胞群体中的内陷。因此，这个程序的作用类似于其他稳态机制，如自噬，允许细胞通过恢复必需的营养物质来应对饥饿压力。在葡萄糖饥饿的条件下，赢家细胞摄取输家， 这表明葡萄糖饥饿诱导了癌症中一种新形式的细胞竞争，据预测，这种竞争对疾病的进展有重大影响。该提案描述了阐明控制饥饿诱导的内陷及其对癌症进展的影响的信号机制的计划。

 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.