In a paper published in PNAS, research carried out by PhD student Ralitsa Madsen and colleagues from Robert Semple’s group (now based in Edinburgh) has identified dose-dependent effects on stemness in response to genetic activation of class IA PI3-kinase (PI3K) and prompts re-evaluation of the widely-held belief that PIK3CA mutations are strictly heterozygous in cancer.
Hyperactivation of the PI3K pathway is a frequent event in human cancer. Oncogenic ‘driver’ mutations in the catalytic PIK3CA subunit also cause the rare developmental disorder PROS. The IMS researchers engineered the first human stem cells with heterozygous or homozygous expression of a PIK3CA mutation that occurs frequently in both PROS and cancer and found that homozygosity but not heterozygosity induces cancer-associated phenotypic changes, including self-sustained stemness.
Madsen says, “Having seen the striking effects of homozygosity in the stem cells, it was impossible not to wonder whether PI3K-associated cancers could have more than one mutant PIK3CA copy. We confirmed this hypothesis by computational analyses, performed in collaboration with the Vanhaesebroeck and McGranahan groups at UCL’s Cancer Institute. Our findings suggest that a PI3K activity threshold determines the pathological consequences of oncogenic PIK3CA activation and provide the first mechanistic insight into the role of this pathway in human pluripotent stem cells.”
This work was supported by Wellcome and the UK NIHR Cambridge Biomedical Centre. We acknowledge excellent support from MRL Core Facility staff, particularly Gregory Strachan (Imaging) and James Warner (Histology).