University of Dundee

'Oncogenic PI3Kα corrupts the temporal encoding of growth factor signals'

Event Date: 
Thursday, September 1, 2022 - 10:00 to 11:00
Event Location: 
Small Lecture Theatre: Medical Sciences Institute, SLS
Host: 
Professor Dario Alessi FRS FRSE FMedSci
Event Speaker: 
Dr Ralitsa Madsen
Institution: 
Sir Henry Wellcome Fellow, University College London Cancer Institute
Event Type: 
Seminar
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MRC Protein Phosphorylation and Ubiquitylation Unit Spotlight Seminar 

 

Bio:  

 

Following her PhD in Metabolic and Cardiovascular Disease at the Institute of Metabolic Science, Cambridge, Ralitsa Madsen is now a Sir Henry Wellcome Postdoctoral Fellow at UCL Cancer Institute, with Prof Bart Vanhaesebroeck as her primary research sponsor. Ralitsa’s research aims to develop a quantitative understanding of class IA PI3K signalling, by bridging the gap between conventional cell biology and computational modelling. She has a particular interest in understanding how disease-associated, activating mutations in the PI3Ka isoform result in corrupted biochemical information transmission. This is facilitated by systems biology approaches, in collaboration with her secondary research sponsors Prof Julio Saez-Rodriguez (Heidelberg) and Dr Chris Tape (UCL). Ralitsa has also spent part of her fellowship in Prof Alex Toker’s laboratory (BIDMC, Harvard Medical School), using multi-omic and network biology methods to help characterise a novel second-generation AKT degrader. Apart from her daily research, Ralitsa was recently appointed member of the inaugural UK Committee on Research Integrity (UK CORI) for a 3-year-term period. She is an avid Open Research advocate, regularly taking part in national and global efforts to promote reproducibility in science.

 

 

Abstract:

 

Cellular information transmission relies upon quantitative integration of temporally and spatially distinct signaling modalities, akin to a signaling “code”.  Subtle perturbations of this code can translate into widespread phenotypic abnormalities, as shown recently in my own work with human pluripotent stem cells harbouring distinct allelic doses of the frequently observed cancer variant PIK3CAH1047R. While this and other activating PIK3CA mutations result in potent baseline activation of the catalytic p110α subunit of phosphoinositide 3-kinase alpha (PI3Kα), if and how they may corrupt growth factor (GF)-specific signal encoding remains unstudied. To address these questions, I have developed systematic, quantitative single-cell analyses of PI3K signalling. These feature optimised high-density kinetic studies of growth factor-induced PI3Ka activation by TIRF microscopy of phosphoinositide biosensors, using CRISPR-edited cell models with endogenous expression of hyperactive or inactive PI3KaComplementary studies rely on high-throughput mass cytometry-based analyses of single-cell PI3K signalling in a novel 3D-based system, with high temporal resolution enabled by multiplexing. Using these approaches, I have discovered that both oncogenic PI3Ka activation as well as complete loss-of-function (akin to high-dose pharmacological inhibition in a clinical setting) decrease the cell’s ability to distinguish specific growth factors, thus leading to corrupted biochemical information transmission. I will discuss these findings as well as ongoing experiments that aim to demonstrate that successful pharmacological targeting of this signalling pathway will require correction of signalling dynamics as opposed to complete ablation of the activity of the signal transducer.