ABSTRACT
Experimental inactivation of certain genes involved in metabolism attenuates cancer cell growth in vitro. 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 affecting metabolic pathways do not necessarily result in a functional defect because affected cells may be rescued by exchanging metabolites 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 the constitutively expressed Cx26. In co-cultures of wild-type cells with cells that had inactivated components of pH regulation (SLC9A1), glycolysis (ALDOA), or mitochondrial metabolism (NDUFS1), we show that diffusive coupling was able to rescue the functional defect associated with the inactivation of metabolite-handling genes. Function rescue was dependent on Cx26 channels and reduced phenotypic heterogeneity among cells. Since the phenotypic landscape did not map onto genotype, an individual cell should not be considered as the unit under selection, at least in the case of metabolite-handling processes. Our findings can explain why certain loss-of-function mutations in genes, previously ascribed as being ‘essential’, do not influence the growth of human cancers.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Authors declare no conflicts of interest
