Do nutrient availability and the extracellular matrix affect therapy response in cancer?

The tumour microenvironment (TME) plays a pivotal role in controlling cancer progression and response to therapy. A key component of the TME is the extracellular matrix (ECM), a complex network of secreted protein involved in controlling a variety of cell functions, including proliferation and migration. Due to the elevated tumour growth rate and limited blood supply, the TME is often hypoxic and nutrient deprived. This drives adaptations in cancer cells, allowing them to thrive in this sub-optimal environment. Our lab has recently demonstrated that breast cancer cells ‘feed’ on the ECM, by internalising it and degrading it in the lysosomes. We found that this process was required to support cancer cell growth and migration under nutrient starvation conditions (Nazemi et al., 2024; Llanses Martinez et al., 2024). However, it is not clear whether nutrient availability and ECM internalisation also play a role in the emergence of drug resistance in cancer. Our preliminary data indicate that nutrient starvation, in the presence of ECM, confers resistance to a variety of inhibitors in both breast and pancreatic cancer cells. Therefore, this project aims at characterising the role of nutrient availability and of the ECM in promoting drug resistance and it’s composed of 3 objectives: – Characterisation of the effect of different nutrient starvation conditions and ECM components to the response of cancer cells to standard chemotherapy drugs and targeted treatments – Elucidation of the molecular mechanisms through which both nutrient availability and the ECM dictate drug responses – Investigation of cancer cell behaviour in more complex 3D systems, including tumour-derived organoids Together, this project will identify novel mechanisms driving drug resistance, resulting in the identification of new targets which could sensitise cancer cells to current therapies. Several techniques will underpin this work, including 2D and 3D cell culture, generation of complex ECMs, metabolomics and proteomics approaches and a variety of imaging techniques, including high-throughput, confocal and live cell imaging.