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.
Entosis was identified as a mechanism responsible for the formation of 'cell-in-cell' structures that have observed for decades in various human cancers, such as breast, colon, and pancreatic carcinoma. We now find that entosis is induced by metabolic stress, suggesting that this mechanism may support tumor progression by following cells to adapt to nutrient deprivation, and may be induced by therapies that disrupt nutrient signaling or uptake. The proposed work seeks to understand a novel mechanism that promotes the progression of some of the most common and deadliest human cancers.
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