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Metabolic context regulates the competitive fitness of oncogenic PIK3CA mutant clones in the normal esophagus

Activating mutations in PIK3CA generate large clones in the aging human esophagus. Here we investigate the underlying cellular mechanisms regulating their expansion by lineage tracing. Expression of an activating heterozygous Pik3caH1047R mutation in single progenitor cells of the mouse esophagus tilts cell fate towards proliferation, generating mutant clones that outcompete their wild type neighbours. The mutation leads to increased aerobic glycolysis through the activation of Hif1α transcriptional targets. In vitro and in vivo interventions that level out differences in activation of the PI3K/HIF1α/aerobic glycolysis axis between wild type and Pik3caH1047R cells attenuate the competitive advantage of the mutants. In contrast, metabolic conditions that alter Insulin/PI3K signalling, such as type-1 diabetes or diet-induced insulin resistance, further increase Pik3caH1047R mutant competitiveness in mice. Consistently, the density of activating PIK3CA mutations in human esophagus is increased in overweight individuals. We conclude that the metabolic environment influences the mutational landscape of normal epithelia. Clinically feasible interventions that even out signalling imbalances between wild type and mutant cells may therefore limit the expansion of oncogenic mutants in normal tissues.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001001933 Other

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00005563767 bam 8.4 MB
EGAF00005563768 bam 9.0 MB
EGAF00005563769 bam 8.8 MB
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EGAF00005563793 bam 4.0 MB
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EGAF00005563886 bam 6.6 MB
EGAF00005563887 bam 7.5 MB
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EGAF00005563902 bam 6.6 MB
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EGAF00005563927 bam 9.2 MB
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EGAF00005563932 bam 13.4 MB
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EGAF00005563942 bam 12.9 MB
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EGAF00005563948 bam 10.8 MB
EGAF00005563949 bam 11.4 MB
EGAF00005563950 bam 9.9 MB
EGAF00005563951 bam 9.6 MB
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EGAF00005563953 bam 10.2 MB
EGAF00005563954 bam 9.8 MB
EGAF00005563955 bam 10.2 MB
EGAF00005563956 bam 10.0 MB
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EGAF00005563958 bam 12.0 MB
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EGAF00005563961 bam 9.8 MB
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EGAF00005563963 bam 10.9 MB
EGAF00005563964 bam 10.2 MB
EGAF00005563965 bam 9.9 MB
EGAF00005563966 bam 10.5 MB
EGAF00005563967 bam 9.7 MB
EGAF00005563968 bam 9.7 MB
EGAF00005563969 bam 9.4 MB
EGAF00005563970 bam 9.8 MB
EGAF00005563971 bam 10.0 MB
EGAF00005563972 bam 9.7 MB
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EGAF00005563978 bam 7.7 MB
EGAF00005563979 bam 9.9 MB
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EGAF00005563987 bam 9.0 MB
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EGAF00005563989 bam 8.4 MB
EGAF00005563990 bam 7.9 MB
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EGAF00005564004 bam 11.1 MB
EGAF00005564005 bam 10.9 MB
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EGAF00005564020 bam 8.3 MB
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EGAF00005564023 bam 8.9 MB
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EGAF00005564026 bam 9.9 MB
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EGAF00005564028 bam 9.2 MB
EGAF00005564029 bam 9.7 MB
EGAF00005564030 bam 8.7 MB
EGAF00005564031 bam 10.0 MB
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EGAF00005564033 bam 8.0 MB
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EGAF00005564035 bam 8.0 MB
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EGAF00005564064 bam 10.1 MB
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EGAF00005564473 bam 7.2 MB
707 Files (5.5 GB)