Mapping changes in cellular information transfer underlying cell-fate decisions triggered by oncogenes

Improved understanding of the mechanisms that underlie cell-fate decisions is critical not only to identifying the molecular determinants of disease but also to the future development of cell-based therapies. In particular, the accumulation of mutations during the development of cancer subverts normal cell-fate decisions, leading to the outgrowth of specific clones creating the characteristic heterogeneity observed in tumours. The proposed project will combine novel technologies for single-cell digital imaging, with network modeling and informatics, to investigate how oncogenes rewire signalling networks (e.g. RAS and RAS-dependent signal transduction networks) to alter-often in subtle ways-cell-fate decisions contributing to tumorigenesis. The outputs of the proposed work are relevant to the priority areas of Digital Technologies for Healthcare, Advanced Therapeutics besides Accelerating Medicines Discovery, and the project will provide training in these areas.

Project:
Cell signalling, cell fate choices and the process of transformation exhibit significant variability within identical clones (non-genetic heterogeneity), both during normal differentiation and in diseases like cancer. Therefore, we will develop an innovative single-cell systems biology approach to study signalling networks triggered by activation of the key mediator, KRAS, to investigate the role of non-genetic heterogeneity during early oncogenesis. Different activating mutations in KRAS have been linked to cell-fate decisions that steer cancer development in different directions, but the mechanisms by which different KRAS mutations (e.g., KRAS mutations at codon 12) alter cell behaviour, and their implications to disease, are largely uncharacterized. We will investigate the hypothesis that the alternative rewiring of RAS-dependent signalling pathways (mediated by effectors such as MAPK, PI3K and RAL GDS) by different KRAS mutations induces distinct cell-fate decisions that exhibit non-genetic heterogeneity.

The PhD candidate will utilize standard biochemical and microscopy techniques for the study of signalling and metabolic pathways and how these are altered by different KRAS oncogenic mutations. The work will be integrated with novel single cell multiplexed biochemical imaging that will enable to characterize both genetic and non-genetic heterogeneity. Molecular cloning and cell culture techniques and a general aptitude to work with microscopy tools will be therefore necessary. The PhD candidate will also utilize computational tools (BioModelAnalyzer) to model KRAS signalling network. This will link specific mutations in KRAS downstream signalling effects and serve to explain the causal relationships between mutation effects and specific gene activations.

As part of this project, we will offer an internship in AbCam with the aim to develop novel multiplexed immunofluorescence assays with the long-term goal to translate the finding of this project to the clinic.

The project will offer a unique opportunity to train across disciplines through a strong partnership between an experimental and a computational group in the MRC Cancer Unit, with an industrial partner, AbCam, one of the largest and most successful UK companies with growing interests in using new technologies for advanced therapeutics.