Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes

Kon, Shunsuke; Ishibashi, Kojiro; Katoh, Hiroto; Kitamoto, Sho; Shirai, Takanobu; Tanaka, Shinya; Kajita, Mihoko; Ishikawa, Susumu; Yamauchi, Hajime; Yako, Yuta; Kamasaki, Tomoko; Matsumoto, Tomohiro; Watanabe, Hirotaka; Egami, Riku; Sasaki, Ayana; Nishikawa, Akio; Kameda, Ikumi; Maruyama, Takeshi; Narumi, Rika; Morita, Tomoko; Sasaki, Yoshiyuki; Enoki, Ryosuke; Honma, Sato; Imamura, Hiromi; Oshima, Masanobu; Soga, Tomoyoshi; Miyazaki, Jun‐ichi; Duchen, Michael R.; Nam, Jin Min; Onodera, Yasuhito; Yoshioka, Shingo; Kikuta, Junichi; Ishii, Masaru; Imajo, Masamichi; Nishida, Eisuke; Fujioka, Yoichiro; Ohba, Yusuke; Sato, Toshiro; Fujita, Yasuyuki

doi:10.1038/ncb3509

Cited by 196 publications

(225 citation statements)

References 58 publications

Supporting

Mentioning

205

Contrasting

Order By: Relevance

“…While S1P is also required, it is not produced by WT epithelial cells or extruding cells, as in apoptotic or live cell extrusion (Figure 1); instead, S1P is required in culture serum for Ras V12 cell extrusion, and would thus presumably be derived from some other source in vivo , such as endothelial cells or erythrocytes (Yamamoto et al, 2016). Importantly, ~80% of Ras V12 cell clones are apically extruded/extruding in mouse intestine (Kon et al, 2017), suggesting that competition-mediated extrusion may play an important role in vivo . Supporting this, in the mouse hair follicle stem cell niche, activation of oncogenic HRas in specific clones triggers a competition-like interaction wherein WT cells ultimately surround and expel oncogenic outgrowths into the dermis (Brown et al, 2017).…”

Section: Cell Competition and The Active Extrusion Of Aberrant Cellsmentioning

confidence: 99%

“…Importantly, although the resulting esophagi composed entirely of Notch-inhibited winner cells are morphologically normal, they are primed for tumorigenesis and permit p53-stabilized overgrowths (Alcolea et al, 2014). Although these examples did not monitor cell extrusion, observations of cell extrusion during the competitive removal of oncogenic cells in mouse hair follicles (Brown et al, 2017) and intestines (Kon et al, 2017) make more plausible a role for vertebrate competition-mediated cell extrusion in tumorigenesis.…”

Section: A Force For Evil: Cell Extrusion In Diseasementioning

confidence: 99%

See 1 more Smart Citation

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

View full text Add to dashboard Cite

Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.

show abstract

Section: Cell Competition and The Active Extrusion Of Aberrant Cellsmentioning

confidence: 99%

Section: A Force For Evil: Cell Extrusion In Diseasementioning

confidence: 99%

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

View full text Add to dashboard Cite

show abstract

“…Mechanistically, surrounding normal MDCK cells promote elimination of neighboring Ras or Src cells by accumulating Filamin at the cell–cell interface (Kajita et al., ). The accumulation of Filamin causes EPLIN‐mediated mitochondrial dysfunction in Ras or Src cells, leading to cell extrusion (Kon et al., ; Ohoka et al., ). Importantly, similar cell extrusion mechanism also worked in mouse intestinal epithelia (Kon et al., ).…”

Section: Elimination Of Oncogenic Cells: Tumor‐suppressive Cell Compementioning

confidence: 99%

“…The accumulation of Filamin causes EPLIN‐mediated mitochondrial dysfunction in Ras or Src cells, leading to cell extrusion (Kon et al., ; Ohoka et al., ). Importantly, similar cell extrusion mechanism also worked in mouse intestinal epithelia (Kon et al., ). It was also shown in MDCK cell cultures that Scrib‐knockdown cells cause p38‐depedent cell death when surrounded by normal MDCK cells (Norman et al., ).…”

Section: Elimination Of Oncogenic Cells: Tumor‐suppressive Cell Compementioning

confidence: 99%

Cell competition: Emerging mechanisms to eliminate neighbors

Nagata

Igaki

2018

Dev Growth Differ

View full text Add to dashboard Cite

Cell competition is a context‐dependent cell elimination through short‐range cell–cell interaction, in which cells with higher fitness eliminate neighboring less‐fit or oncogenic cells within the growing tissue. Cell competition can be triggered by many different factors such as heterozygous mutations in the ribosomal protein genes (which are called “Minute” mutations), elevated Myc, Yorkie/YAP, Wg/Wnt, JAK‐STAT, Ras, or Src activity, and loss of Mahjong/VprBP, endocytic pathway components, or apicobasal cell polarity. Studies on the mechanisms and roles of cell competition have suggested that cell competition can be divided into two types: selection of fitter cells or elimination of oncogenic cells. The former type of cell competition includes Minute or Myc‐induced cell competition that is considered to be dependent on the relative level of protein synthesis. The later type of cell competition includes tumor‐suppressive cell competition triggered by loss of cell polarity genes such as scribble (scrib) or discs large (dlg). Genetic studies in Drosophila during the past decade have provided significant progress in understanding the mechanisms of these phenomena. At the same time, these studies have now raised new questions; how do different mechanisms contribute or cooperate to drive cell competition, do common mechanisms exist in different types of cell competition, and what are the physiological roles of these cell competition phenomena?

show abstract

“…Embryonic mouse cells carrying a heterozygous mutation of the riboprotein gene Rpl24 also lose in competitions with embryonic cells bearing two WT Rpl24 alleles (Oliver, Saunders, Tarle, & Glaser, 2004). In adult mouse tissues, cell competition has been induced by differences in Myc in cardiomyocytes, p53 in hematopoietic stem cells, Ras in intestinal epithelial cells and COL17A1 in mouse epidermal stem cells (Bondar & Medzhitov, 2010;Kon, 2018;Kon et al, 2017;Liu et al, 2019;Villa Del Campo, Claveria, Sierra, & Torres, 2014). Cell competition has also been observed in cultured Madin-Darby canine kidney (MDCK) epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E₂ and its receptor EP2 trigger signaling that contributes to YAP‐mediated cell competition

et al. 2020

Self Cite

View full text Add to dashboard Cite

Cell competition is a biological process by which unfit cells are eliminated from “cell society.” We previously showed that cultured mammalian epithelial Madin‐Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by “normal” MDCK cells. However, the molecular mechanism underlying the elimination of active YAP‐expressing cells was unknown. Here, we used high‐throughput chemical compound screening to identify cyclooxygenase‐2 (COX‐2) as a key molecule triggering cell competition. Our work shows that COX‐2‐mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase‐cyclic AMP‐PKA pathway that, in the presence of active YAP, induces E‐cadherin internalization leading to apical extrusion. Thus, COX‐2‐induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.

show abstract

Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes

Cited by 196 publications

References 58 publications

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Cell competition: Emerging mechanisms to eliminate neighbors

Prostaglandin E₂ and its receptor EP2 trigger signaling that contributes to YAP‐mediated cell competition

Contact Info

Product

Resources

About

Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes

Cited by 196 publications

References 58 publications

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Cell competition: Emerging mechanisms to eliminate neighbors

Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP‐mediated cell competition

Contact Info

Product

Resources

About

Prostaglandin E₂ and its receptor EP2 trigger signaling that contributes to YAP‐mediated cell competition