Heterogeneity of treatment response in advanced cancer: role of intrinsic and microenvironmental factors

Summary This project aims to identify and characterise the contribution of tumour-intrinsic and microenvironmental factors in driving the drug resistance of aggressive cancer cell subsets. The project uses tumour organoids derived from colorectal and pancreatic cancer patients.

Project Details

Intra-tumour heterogeneity is a key factor in the ability of tumour cells to escape therapy and fuel tumour regrowth. The plasticity of tumour cell phenotypes impacts on their drug resistance ability and is influenced by the tumour micro environment. Indeed, tumour cell phenotype is under constant remodelling under the competing pressure of intrinsic hardwired(eg genetic) signals and of environmental effectors such as stomal and immunecells, non-cellular matrix components, biophysical parameters (eg density,stiffness). In the context of cancer metastasis, tumour cells must deal with very different environmental conditions compared to what they had to face in their organ of origin. Integrated knowledge of the contributions by intrinsic and extrinsic effectors in shaping intra-tumour heterogeneity would improve our understanding of tumour progression and allow us to determine the impact of each component in treatment response. In this project, we will test the impact of different extracellular matrices and micro environment cells on the growth of tumour organoids grown from colorectal and pancreatic cancer. The response of tumour organoids to standard of care and new drugs will also be characterised in the presence of different micro environmental conditions, and drug combinations targeting different intrinsic or environment-driven pathways will be tested to improve treatment response. To do so, we will use a combination of techniques including 3D cell culture, flow cytometry.