乳上皮細胞におけるオプトジェネティクスによって模倣されたPI3Kシグナル伝達の癌原性変化は、一部の表現型の変化を再現する

Cancer is known to be a disease of altered cellular signaling; however, the relationship between mutation-specific changes to signal transduction and the phenotypic consequences produced remains poorly understood. Here, we investigate two common breast cancer driver mutations, the PIK3CA^H1047R mutation and the ErbB2 amplification, both of which activate the PI3K-Akt pathway but paradoxically drive distinct cellular outcomes. Indeed, in nontransformed mammary epithelial cells, PI3K^H1047R expression induced features of epithelial-mesenchymal transition (EMT), while ErbB2^amp cells exhibited a hyperproliferative phenotype. Characterization of PI3K axis signaling revealed that ErbB2^amp cells display prolonged, stimulus-dependent PI3K activation, whereas PI3K^H1047R cells show constitutive, ligand-independent signaling. To test whether these distinct dynamics contribute to the phenotypic responses, we employed an iLID-based optogenetic system that enables precise, tunable control of endogenous PI3K activity. Using this tool to mimic the mutation-specific dynamics in MCF10A mammary epithelial cells, we found that PI3K signaling patterns alone were sufficient to reproduce key features of the PIK3CA H1047R-associated EMT phenotype but not the ErbB2-associated proliferative phenotype. These findings suggest that the temporal encoding of pathway activity, not merely its magnitude, can drive some phenotypic changes in oncogenic progression, explain how distinct mutations within a common signaling pathway can produce divergent cellular phenotypes, and provide a workflow for interrogating the functional consequences of changes in signaling dynamics.