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Competition between human cells by entosis.

Abstract
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.
AuthorsQiang Sun, Tianzhi Luo, Yixin Ren, Oliver Florey, Senji Shirasawa, Takehiko Sasazuki, Douglas N Robinson, Michael Overholtzer
JournalCell research (Cell Res) Vol. 24 Issue 11 Pg. 1299-310 (Nov 2014) ISSN: 1748-7838 [Electronic] England
PMID25342560 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Amides
  • Enzyme Inhibitors
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Pyridines
  • RAC1 protein, human
  • ROCK1 protein, human
  • ROCK2 protein, human
  • Y 27632
  • Actomyosin
  • rho-Associated Kinases
  • Myosins
  • rac1 GTP-Binding Protein
  • ras Proteins
  • rhoA GTP-Binding Protein
Topics
  • Actomyosin (metabolism)
  • Amides (pharmacology, therapeutic use)
  • Animals
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Down-Regulation
  • Entosis
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • Female
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, SCID
  • Myosins (metabolism)
  • Neoplasms (drug therapy, metabolism, pathology)
  • Proto-Oncogene Proteins (metabolism)
  • Pyridines (pharmacology, therapeutic use)
  • RNA Interference
  • rac1 GTP-Binding Protein (antagonists & inhibitors, genetics, metabolism)
  • ras Proteins (metabolism)
  • rho-Associated Kinases (antagonists & inhibitors, genetics, metabolism)
  • rhoA GTP-Binding Protein (genetics, metabolism)

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