Entosis Is Induced by Glucose Starvation

Abstract

SUMMARY Entosis is a mechanism of cell death that involves neighbor cell ingestion. This process occurs in cancers and promotes a form of cell competition, where winner cells engulf and kill losers. Entosis is driven by a mechanical differential that allows softer cells to eliminate stiffer cells. While this process can be induced by matrix detachment, whether other stressors can activate entosis is unknown. Here, we find that entosis is induced in adherent cells by glucose withdrawal. Glucose withdrawal leads to a bimodal distribution of cells based on their deformability, where stiffer cells appear in a manner requiring the energy-sensing AMP-activated protein kinase (AMPK). We show that loser cells with high levels of AMPK activity are eliminated by winners through entosis, which supports winner cell proliferation under nutrient-deprived conditions. Our findings demonstrate that entosis serves as a cellular response to metabolic stress that enables nutrient recovery through neighbor cell ingestion.

Canine oral primary melanoma cells exhibit shift to mesenchymal phenotype and phagocytic behaviour

“…On the other hand, entosis may promote tumour progression in several ways. It may provide tumour cells with nutrients and thus assure their survival under the starved conditions of the tumour stroma . Entosis may also contribute to immune evasion.…”

“…Three biological factors triggering tumour cell cannibalism have been identified thus far, namely anchorage‐independent growth, aberrant proliferation and starvation, that is, lack of available glucose. Accordingly, it has been proposed that entosis may confer tumour suppression via selective killing of dissociating, hyperproliferative or glucose‐deprived cancer cells, notably at early tumour stages . On the other hand, entosis may promote tumour progression in several ways.…”

The impact of non-genetic heterogeneity on cancer cell death

“…Like autophagy, this mechanism may support the long-term survival of tumour cells when detached from the extracellular matrix or exposed to nutrient starvation (Overholtzer et al 2007; Hamann et al 2017). Entosis occurs spontaneously in certain populations of cancer cells (e.g.…”

“…Entosis occurs spontaneously in certain populations of cancer cells (e.g. MCF-7 breast cancer cells) and can be further enhanced by glucose starvation (Durgan et al 2017; Hamann et al 2017). …”

“…At the molecular level, winner cells exhibit increased mechanical deformability, a phenotype controlled by the activity of the cellular actinomyosin network (Sun et al 2014). In response to glucose starvation, higher levels of AMPK pathway activity may inhibit the cytoskeletal regulator Ras-related C3 botulinum toxin substrate 1 (RAC1) or alter myosin contraction, leading to reduced mechanical deformability and ‘loser’ status (Hamann et al 2017). Thus, susceptibility to entosis may be governed by fluctuations in the metabolic state of the cell, providing a link between heterogeneous glycolytic metabolism/AMPK activity within a cellular population and susceptibility to entotic cell death.…”