Irradiation Selects for p53-Deficient Hematopoietic Progenitors

Marusyk, Andriy; Porter, Christopher C.; Zaberezhnyy, Vadym; DeGregori, James

doi:10.1371/journal.pbio.1000324

Cited by 135 publications

(110 citation statements)

References 47 publications

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“…While the identity of the engulfing cells and whether engulfment itself mediates competition in Drosophila are controversial, we clearly show that neighboring cell-mediated engulfment and killing occur in mixed populations of human cells. Other mechanisms of competition between mammalian cells have been demonstrated, including the differential extrusion of cells of mixed genotypes from monolayer cultures [9,10], competition between cells of the early embryo [36][37][38], and competition between hematopoietic progenitors driven by differences in p53 activity [39,40]. Perhaps diverse competition mechanisms reflect a stringent requirement for homeostasis in different contexts within various tissue types of metazoan organisms during development and adulthood.…”

Section: Discussionmentioning

confidence: 99%

Competition between human cells by entosis

et al. 2014

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Human carcinomas are comprised of complex mixtures of tumor cells that are known to compete indirectly for nutrients and growth factors. Whether tumor cells could also compete directly, for example by elimination of rivals, is not known. Here we show that human cells can directly compete by a mechanism of engulfment called entosis. By entosis, cells are engulfed, or cannibalized while alive, and subsequently undergo cell death. We find that the identity of engulfing ("winner") and engulfed ("loser") cells is dictated by mechanical deformability controlled by RhoA and actomyosin, where tumor cells with high deformability preferentially engulf and outcompete neighboring cells with low deformability in heterogeneous populations. We further find that activated Kras and Rac signaling impart winner status to cells by downregulating contractile myosin, allowing for the internalization of neighboring cells that eventually undergo cell death. Finally, we compute the energy landscape of cell-in-cell formation, demonstrating that a mechanical differential between winner and loser cells is required for entosis to proceed. These data define a mechanism of competition in mammalian cells that occurs in human tumors.

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Section: Discussionmentioning

confidence: 99%

Competition between human cells by entosis

et al. 2014

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“…The key tumour suppressor protein, p53 prevents cancer through multiple mechanisms 45 . In a transplantable mouse model of lymphoma, deletion of p53 from hematopoietic progenitors per se does not confer a competitive advantage over wild-type cells unless the system is stressed (in this case by irradiation) 46,47 . p53-deficient cells survive irradiation whereas wild-type cells are eliminated by p53 activity (either through apoptosis, cell cycle arrest or senescence).…”

Section: Apoptosis Cell Competition and Cancermentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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“…Recently, three elegant studies have highlighted a role for p53 in regulating the competitive selection of stem and progenitor cells (HSPCs following the stress of ionizing radiation (IR) [59][60][61]. After IR, cells with lower levels/ activity of p53 outgrew those with higher levels/activity.…”

Section: Opinionmentioning

confidence: 99%