Solute exchange through gap junctions lessens the adverse effects of inactivating mutations in metabolite-handling genes
- University of Oxford, United Kingdom
Abstract
Growth of cancer cells in vitro can be attenuated by genetically inactivating selected metabolic pathways. However, loss-of-function mutations in metabolic pathways are not negatively selected in human cancers, indicating that these genes are not essential in vivo. We hypothesize that spontaneous mutations in 'metabolic genes' will not necessarily produce functional defects because mutation-bearing cells may be rescued by metabolite exchange with neighboring wild-type cells via gap junctions. Using fluorescent substances to probe inter-cellular diffusion, we show that colorectal cancer (CRC) cells are coupled by gap junctions assembled from connexins, particularly Cx26. Cells with genetically inactivated components of pH regulation (SLC9A1), glycolysis (ALDOA), or mitochondrial respiration (NDUFS1) could be rescued through access to functional proteins in co-cultured wild-type cells. The effect of diffusive coupling was also observed in co-culture xenografts. Rescue was largely dependent on solute exchange via Cx26 channels, a uniformly and constitutively expressed isoform in CRCs. Due to diffusive coupling, the emergent phenotype is less heterogenous than its genotype, and thus an individual cell should not be considered as the unit under selection, at least for metabolite-handling processes. Our findings can explain why certain loss-of-function mutations in genes ascribed as 'essential' do not influence the growth of human cancers.
Data availability
Fig 1 - original sequencing data is available from the reference given in text. A tabulated form of 1E is given as a supplementary Table.All original data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided.
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Replication error deficient and proficient colorectal cancer gene expression differences caused by 3'UTR polyT sequence deletionshttps://doi.org/10.1073/pnas.1015604107.
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Spatiotemporal analysis of human intestinal development at single-cell resolutionhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116222.
Article and author information
Author details
Gulnar Abdullayeva
Funding
European Research Council (723997)
- Pawel Swietach
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jean X Jiang, The University of Texas Health Science Center at San Antonio, United States
Ethics
Animal experimentation: This study was performed in accordance with the provisions of the Animals (Scientific Procedures) Act 1986 and recommendations set by the Biomedical Services unit at Oxford University. All work involving mice obtained approval of ethics and welfare board instructions, and was authorized by Project Licence PPL P01A04016 issued by the UK Home Office. All surgery was performed under anesthesia, and appropriate post-recovery care was provided to minimize suffering.
Version history
- Received: March 7, 2022
- Preprint posted: March 16, 2022 (view preprint)
- Accepted: September 13, 2022
- Accepted Manuscript published: September 15, 2022 (version 1)
- Version of Record published: October 5, 2022 (version 2)
Copyright
© 2022, Monterisi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Solute exchange through gap junctions lessens the adverse effects of inactivating mutations in metabolite-handling genes
eLife 11:e78425.
https://doi.org/10.7554/eLife.78425
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