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26.07.17 'Loser' cell status results from JNK JAK/STAT and oxidative stress signalling pathways

last modified Jul 26, 2017 11:21 AM
The Piddini lab pinpoint which signalling pathways are responsible for making 'loser' cells, in this Nature Communications paper
26.07.17  'Loser' cell status results from JNK JAK/STAT and oxidative stress signalling pathways

Proposed model for the contribution of JNK, JAK/STAT and Nrf2 pathways to cell competition (Fig. 7 from the paper).

Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status

Kucinski I et al. (2017) Nature Communications 8, Article number: 136

DOI: 10.1038/s41467-017-00145-y

 

Author's summary

Eugenia Piddini and her team have carried out a detailed analysis of cells that are killed by other cells during cell competition (so-called ‘losers’). In this article published in Nature Communications they identify new signalling pathways that are hallmarks of loser cells, and characterise how they contribute to the loser status. 

A key discovery emerging from their work is that activation of the oxidative stress response is sufficient to turn cells into losers and be killed off by their neighbours. This is interesting because the oxidative stress response is normally activated in cells as a way to protect themselves from oxidative insults. “What we found”, says Professor Piddini, “is that activating the oxidative stress response in cells serves a dual purpose. On the one hand, as it is well established, it acts as a pro-survival adaptation response. On the other hand, however, it primes cells for elimination by neighbouring cells that are not undergoing oxidative stress and are not activating this response.” 

Oxidative stress is a hallmark of several pathologies including neurodegenerative diseases and cancer. “If the findings from our Drosophila work also hold for mammalian cells this might help us understand the onset and spread of these diseases”, says Professor Piddini.

 

Abstract from the paper

Cell competition is a form of cell interaction that causes the elimination of less fit cells, or losers, by wild-type (WT) cells, influencing overall tissue health. Several mutations can cause cells to become losers; however, it is not known how. Here we show that Drosophila wing disc cells carrying functionally unrelated loser mutations (Minute and mahjong) display the common activation of multiple stress signalling pathways before cell competition and find that these pathways collectively account for the loser status. We find that JNK signalling inhibits the growth of losers, while JAK/STAT signalling promotes competition-induced winner cell proliferation. Furthermore, we show that losers display oxidative stress response activation and, strikingly, that activation of this pathway alone, by Nrf2 overexpression, is sufficient to prime cells for their elimination by WT neighbours. Since oxidative stress and Nrf2 are linked to several diseases, cell competition may occur in a number of pathological conditions.

 

Read more about the research previously done here in the Piddini lab.

 

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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