decipheriNg Oncogenic SIgnalling patterns to break CAncer drug Resistance

ended

Despite significant progress in drug therapies for breast cancer, about one fourth of patients still do not survive the disease. Modern, targeted therapies have been proposed to cure the more advanced and aggressive cases of breast cancer. However, non-genetic and genetic mechanisms of drug resistance currently limit the promise of targeted therapy. NOSCAR aims to define the oncogenic Ras/Erk and PI3K/Akt signalling states relevant to breast cancer oncogenic mutations, and delineate the mechanisms which enable development of cancer resistance to targeted therapies. NOSCAR’s objectives are: Using a quantitative cell biology framework that combines a multiplexed biosensor system that reports on Erk/Akt dynamics at single cell level, computer vision, and statistical modelling, I will: (1) produce an atlas of single-cell Erk/Akt dynamic signalling patterns that are associated with a compendium of clinically-relevant breast cancer mutations; (2) measure the signalling states in cells perturbed with clinically-relevant drugs that target different components of the Ras/Erk and PI3K/Akt pathways to evaluate how the oncogenic signalling network is rewired by drug treatment; (3) measure signalling dynamics in 3D spheroid cultures and patient-derived organoids to explore how a self-organizing cellular ecosystem can spatially control signalling at the single cell level to locally control fate decisions, and how the latter process is compromised by an oncogenic mutation. This will provide new insights about tumor heterogeneity and signaling network structures that confer robustness against drug perturbations. We expect to identify vulnerabilities that might be efficiently targeted by drug combinations, providing new avenues to treat breast cancer. The planned research together with training and mentoring that I will receive thanks to the fellowship, will enable to successfully restart my career in research and will significantly benefit my further academic career prospects.