Monday, May 6th, 2024 - 11:15 - Baltzerstrasse 4, C161
Dr. Ralitsa Madsen | University of Dundee | "Embracing complexity: PI3K signalling through a systems lens"
Abstract: Pathological activation of the PI3K/AKT pathway is among the most frequent defects in human cancer and is also the cause of rare overgrowth disorders. Yet, until recently, technical challenges have limited advances in our understanding of the quantitative flow of information within PI3K/AKT signalling and how it is perturbed by disease-causing mutations. I will present our recent development of scalable, single-cell approaches for systematic analyses of signal processing within the PI3K pathway. Using genetically-engineered human cell models with allele dose-dependent expression of PIK3CAH1047R, we have found that this oncogene is not a simple, constitutive pathway activator but a context-dependent modulator of dynamic signal encoding. PIK3CAH1047R reduced quantitative information transfer downstream of IGF1 while selectively enhancing EGF-induced signalling and transcriptional responses. This leads to a gross reduction in signalling specificity, akin to “blurred” signal perception. I will conclude by discussing how these findings and our knowledge of PIK3CA-related overgrowth disorders inform the setup of robust experimental models of aberrant PI3K signalling and, ultimately, therapeutic targeting.
