Cell competition in mouse NIH3T3 embryonic fibroblasts controlled by Tead activity and Myc

Abstract

Cell competition is a short-range communication originally observed in Drosophila. Relatively little is known about cell competition in mammals or in non-epithelial cells. Hippo signaling and its downstream transcription factors of the Tead family, control cell proliferation and apoptosis. Here, we established an in vitro model system that shows cell competition in mouse NIH3T3 embryo fibroblast cells. Co-culture of Tead-activity-manipulated cells with normal (wild-type) cells caused cell competition. Cells with reduced Tead activity became losers, whereas cells with increased Tead activity became super-competitors. Tead directly regulated Myc RNA expression, and cells with increased Myc expression also became super-competitors. At low cell density, cell proliferation required both Tead activity and Myc. At high cell density, however, reduction of either Tead activity or Myc was compensated for by an increase in the other, and this increase was sufficient to confer 'winner' activity. Collectively, NIH3T3 cells have cell competition mechanisms similar to those regulated by Yki and Myc in Drosophila. Establishment of this in vitro model system should be useful for analyses of the mechanisms of cell competition in mammals and in fibroblasts.

Cell competition: Emerging mechanisms to eliminate neighbors

“…In Drosophila , mutations in the components of the tumor‐suppressor Hippo pathway, such as expanded , fat , salvador , hippo , warts , and mats , turned cells to be supercompetitors that eliminate surrounding wild‐type cells (Tyler et al., ). Supercompetition by Hippo pathway mutant cells was also observed in cultured mammalian fibroblast cells (Mamada, Sato, Ota, & Sasaki, ). Importantly, the transcriptional co‐activator Yorkie, a downstream of effector of the Hippo pathway, induces myc expression (Neto‐Silva, De Beco, & Johnston, ), suggesting that Hippo‐mediated supercompetition could be driven by Myc‐induced cell competition.…”

“…In Drosophila, mutations in the components of the tumorsuppressor Hippo pathway, such as expanded, fat, salvador, hippo, warts, and mats, turned cells to be supercompetitors that eliminate surrounding wild-type cells (Tyler et al, 2007). Supercompetition by Hippo pathway mutant cells was also observed in cultured mammalian fibroblast cells (Mamada, Sato, Ota, & Sasaki, 2015). Importantly, Minute cell competition (Akai, Igaki, & Ohsawa, 2018).…”

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

“…The YAP (5SA) mutant protein, in which these five key Ser residues are replaced with Ala, becomes constitutively active. In mouse fibroblast NIH3T3 cells, cell competition resulting in apoptosis was reportedly dependent on TEAD activity (Mamada, Sato, Ota, & Sasaki, ). We subsequently showed that MDCK cells and mouse hepatocytes also undergo YAP‐induced competition (Chiba et al, ; Miyamura et al, ).…”

Hippo pathway controls cell adhesion and context‐dependent cell competition to influence skin engraftment efficiency

“…When transformed cells establish themselves beside normal epithelial cells, the latter are capable of recognizing the invaders and killing or eliminating them without the aid of the immune response (18). Fibroblasts also have the ability to win such cell competitions (19). Thus, defining the mechanisms underlying cell competition may increase our understanding of normal embryogenesis, tumor elimination and progression, and transplantation medicine.…”

“…However, the situation is variable in mammals. When mouse nonepithelial cells with low TEAD activity are cocultured with cells with high TEAD activity, the latter become the winners (19). In contrast, Madin-Darby canine kidney (MDCK) cells that overexpress active YAP1 become losers in competition with WT cells and are removed by apical extrusion (38).…”