Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Swietach Group scientists have identified a rescue mechanism that allows cancers to overcome the consequences of inactivating mutations in critically important genes.

Co-culture of DLD1 cells loaded with spectrally-distinct fluorescent dyes, showing mixing of colours due to exchange across gap junctions. This mechanism also exchanges small-molecule metabolites across the cellular network.

Gene mutations can give rise to cancer if they offer a survival advantage, such as a means of overcoming normal checks on growth. Over time, such mutations are positively selected and become enriched in human tumours. Indeed, many of these mutations are used to diagnose cancers. 

Since gene mutations are random, not all are advantageous and some may even be harmful to cancer cells by inactivating critically-important pathways. Previous in vitro studies have identified multiple metabolic pathways that are essential for cancer cell growth, and proposed that blocking these would be therapeutic. A prediction borne from these studies is that loss-of-function mutations in essential genes should undergo negative selection, and thus not appear in human cancers. However, the phenomenon of negative selection is exceedingly rare in human cancers. This paradox suggests that cancer cells are somehow protected from inactivating mutations in critically important pathways. Swietach group researchers have now described a mechanism that may underpin this rescue of cancerous cells.

In their study, cancer cells that were made deficient in certain enzymatic or transport activities could have their phenotype ‘rescued’ by gaining access to wild-type proteins in neighbouring cells. This rescue occurs through the exchange of solutes across gap junctions, and Cx26 emerges as a particularly important gap junctional channel.  Thus, a syncytial network of cancer cells can be protected from spontaneously inactivating mutations in certain critical genes.

Senior author Professor Pawel Swietach said: “This finding is exciting because it can explain, at least in part, the mismatch between in vitro and in vivo observations on cancers. We often think of individual cancer cells as being the units under selection, a bit like an individual animal in a herd that responds to selection pressures. However, the connectivity among cancer cells means that this logic is an over-simplification. It also predicts that by inhibiting the network behaviour, cancers may become more vulnerable to interventions that target essential pathways. This may greatly increase the efficacy of current metabolic therapies”.

The full paper “Solute exchange through gap junctions lessens the adverse effects of inactivating mutations in metabolite-handling genes”, first authored by Dr Stefania Monterisi, is available to read in eLife.

Similar stories

Professor Dame Sue Black to deliver 2022 Christmas Lectures

In the 2022 Christmas Lectures from the Royal Institution, DPAG's Visiting Professor of Forensic Anatomy Dame Sue Black will share secrets of forensic science.

Randy Bruno and Scott Waddell receive Wellcome Discovery Awards

Congratulations are in order for Professors Randy Bruno and Scott Waddell who have each been awarded a prestigious Wellcome Trust Discovery Award to significantly enhance our understanding of higher cognitive functions.

Anant Parekh to deliver The Physiological Society's Annual Review Prize Lecture

The Annual Review Prize Lecture is The Physiological Society's most prestigious lecture.

Researchers discover novel form of adaptation in the auditory system

DPAG’s auditory neuroscience researchers have found that the auditory system adapts to the changing acoustics of reverberant environments by temporally shifting the inhibitory tuning of cortical neurons to remove reverberation.

Collaborative team driven by DPAG and Chemistry awarded RSC Horizon Prize

The Molecular Flow Sensor Team, with collaborating members principally from DPAG’s Robbins and Talbot groups and the Department of Chemistry, has been named the winner of the Royal Society of Chemistry’s (RSC) Analytical Division Horizon Prize for the development of a new technology for measuring lung function.