AbstractCell competition is an evolutionarily conserved process where cells compete and eliminate each other based on their relative fitness. In this interaction the fitter cells, termed “winners”, eliminate less-fit “loser” cells, and increase proliferation to occupy the newly acquired niche. Cell competition is involved in various biological processes, including cancer, but despite its early discovery many aspects of what drives cells to compete remain elusive. Loser cells regularly exhibit chronic activation of stress signalling pathways such as the Unfolded protein response (UPR) and the oxidative stress response, making them useful markers for competition. They also play an active role in driving the loser status, where for example, overexpression of Nrf2, a component of the oxidative stress response is sufficient to confer the loser status in Drosophila. To understand how Nrf2 mediates the loser status, our lab investigated downstream targets of Nrf2 in a preliminary screen.
From the screen, the bZIP transcription factor: Abrupt emerged as a strong candidate as the expression of an abrupt-RNAi line (KK) in Drosophila wing-discs caused hyperactivation of both the UPR and Nrf2 and rapid elimination by surrounding WT cells in mosaic tissue. It was however later discovered that the effects mediated by the RNAi were due to an off-target effect, which we’ve yet to identify. Transcriptional analysis of abrupt-RNAi (KK) expressing cells showed that Xrp1, an established mediator of cell competition, was highly upregulated. This suggests that the abrupt-RNAi (KK) line may drive cell competition through upregulation of Xrp1. Overexpression of the “long” isoform of Xrp1(Xrp1Long) caused chronic activation of stress pathways and rapid cell death while the “Short” isoform (Xrp1Short) had no effect, suggesting the competitive function of Xrp1 may be isoform dependent. Inhibition of the Nrf2-kinase PERK, alleviated loser cells from UPR signalling, but did not rescue them from Nrf2 activation.
|Date of Award||23 Mar 2021|
|Supervisor||James J L Hodge (Supervisor) & Eugenia Piddini (Supervisor)|
- cell competition