Recently a mechanism was described whereby human cells internalize into neighboring cells, called entosis. Entosis underlies the formation of 'cell-in-cell'structures, where viable cells are engulfed inside of others. These unusual cell structures have been reported in human tumors for decades, but their physiological role remains unknown. Entosis is induced by detachment of cells from extracellular matrix in vitro, and is prevalent in anchorage-independent growth assays in soft agar. In breast tumors, cell-in- cell structures are found in early-stage (DCIS) tumors, and also in late stage invasive tumors, in matrix-deprived regions, suggesting that this process could affect the formation or metastatic spread of cancers. Although cells internalized by entosis are initially viable, most eventually undergo cell death, suggesting that entosis could be a mechanism of tumor suppression. Cell death occurs by a nonapoptotic mechanism that can eliminate cells which are resistant to apoptosis. Entosis may therefore act as a backup or cooperative tumor suppressive mechanism to apoptosis to prevent transformed growth. The identification of this cellular program, whose evidence in vivo far predates the in vitro mechanism, was made possible only by real-time imaging of a classical assay of tumorigenicity, where the basic cellular programs that control the ability to grow are not defined. This proposal describes plans to examine tumorigenic transformation by real-time imaging, to elucidate the molecular mechanisms of entosis, and to examine the role of this process in human cancers.

Public Health Relevance

As cell-in-cell structures are reported in a variety of cancers, such as breast, colon, and lung, the elucidation of the entosis mechanism has the potential to uncover a previously overlooked basic cell biological aspect of some of the most common, and deadliest human cancers. Because the design of new cancer therapies is often tied to mechanistic information about how cell death works in tumor cells, understanding entosis could provide insight into new strategies for how these cancers might be treated.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Intercellular Interactions (ICI)
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Salnikow, Konstantin
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Hamann, Jens C; Overholtzer, Michael (2017) Entosis enables a population response to starvation. Oncotarget 8:57934-57935
Hamann, Jens C; Surcel, Alexandra; Chen, Ruoyao et al. (2017) Entosis Is Induced by Glucose Starvation. Cell Rep 20:201-210
Durgan, Joanne; Tseng, Yun-Yu; Hamann, Jens C et al. (2017) Mitosis can drive cell cannibalism through entosis. Elife 6:
Krishna, Shefali; Overholtzer, Michael (2016) Mechanisms and consequences of entosis. Cell Mol Life Sci 73:2379-86
Florey, O; Kim, S E; Overholtzer, M (2015) Entosis: Cell-in-Cell Formation that Kills Through Entotic Cell Death. Curr Mol Med 15:861-6
Jiang, Xuejun; Overholtzer, Michael; Thompson, Craig B (2015) Autophagy in cellular metabolism and cancer. J Clin Invest 125:47-54
Florey, Oliver; Gammoh, Noor; Kim, Sung Eun et al. (2015) V-ATPase and osmotic imbalances activate endolysosomal LC3 lipidation. Autophagy 11:88-99
Overholtzer, Michael; Wang, Xiaoning (2015) Cell-in-Cell: A Century-Old Mystery Comes to the Table. Curr Mol Med 15:802-4
Nair-Gupta, Priyanka; Baccarini, Alessia; Tung, Navpreet et al. (2014) TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation. Cell 158:506-21
Sun, Qiang; Luo, Tianzhi; Ren, Yixin et al. (2014) Competition between human cells by entosis. Cell Res 24:1299-310

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