Microenvironment
The TME is composed of cancer-associated stromal cells, extracellular matrix (ECM) and a dysfunctional vascular/lymphatic network. Together, these diverse components support cancer progression and therapeutic resistance. To disrupt the supportive TME of breast cancer, we are developing ECM arrays using native tissues from mouse models, with patient samples in the pipeline. By applying decellularisation approaches, we capture the native ECM from tissues and organs, as well as cell-derived matrices from individual cell types, to allow side-by-side comparison in a spot-array format. Seeding cancer cells on these “native” ECM arrays, we can interrogate the sensitivity of cancer cells on different ECM combinations and delve deeper into the compositional cues that support therapy resistance.
Metastasis
The dysfunctional vascular network of solid tumours supplies nutrients, but also provides a route for systemic dissemination. While the classical model metastatic progression involves first invasion, then breaching of the vasculature and eventually metastatic dissemination, the temporal dynamics for intravasation of viable cells are poorly defined. To this end, we are developing probes for intravasation for intravital microscopy in live mouse tumours, as well as to capture intravasation sites to investigate the molecular players through various -omics approaches. In parallel, we are using invasion models to assess the changes that occur in the cell membrane as cancer cells switch to an invasive state in order to capture those changes and identify the earliest timepoints when they appear. The overarching goal being to understand of the changes that occur in order for cancer cells to invade and ultimately intravasate, and ultimately to apply that knowledge to clinical samples to develop biomarkers for metastatic disease.