Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology

Alice Tsuboi,Shizue Ohsawa,Daiki Umetsu,Yukari Sando,Erina Kuranaga,Tatsushi Igaki,Koichi Fujimoto

doi:10.1016/j.cub.2018.05.029

Alice Tsuboi, Shizue Ohsawa + Show 5 more

Open Access

https://doi.org/10.1016/j.cub.2018.05.029

Copy DOI

Abstract

During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation.

Highlights

Primary tumors originate from a single transformed cell containing oncogenic mutations despite being spatially confined by surrounding normal tissue
Using generalized mechanical simulations and in vivo imaging of Drosophila oncogenic clones, we show when and how winner cells selectively expand to compensate for local tissue volume loss after apoptosis of a loser cell
We found that the winners’ expansion was mediated by the anisotropic deformation of dying loser cells (Figure 1); the acquired area of ykiS111AS168AS250A:V5 wild-type in vivo (Yki) or RasV12 winner cells positively correlated with anisotropy of dying loser cells (Figures S4A and S4J) that were oriented in parallel to the clone boundary

Summary

Introduction

Primary tumors originate from a single transformed cell containing oncogenic mutations despite being spatially confined by surrounding normal tissue. It is increasingly apparent that oncogenic cell spread within tissue is driven by a higher rate of proliferation, and by a phenomenon called ‘‘cell competition’’ [1, 2]. Because inhibiting loser apoptosis is sufficient to halt winner spread [1, 2, 5, 8, 9], loser apoptosis seems to play an active role in promoting winner spread within the tissue. It is unclear how loser apoptosis impacts surrounding cells to produce selective occupation by winner cells

Methods

Results

Discussion

Conclusion