3D Microenvironments to Investigate Pancreatic Cancer Cell Migration

Pancreatic cancer is among the most deadly and metastatic cancers. Pancreatic tumours have an unusually stiff and dense stroma that might serve as both a barrier and promoter of metastasis. This project will develop tools to investigate the molecular mechanisms of pancreatic cancer cell invasion and metastasis, combining bioengineering and cell biology to gain insights into how pancreatic cancer cells invade and metastasise.

The complexity of native stroma prevents detailed molecular analysis, but bioengineered substrates offer a chance to manipulate the matrix in a well-defined way to determine molecular mechanisms. Hydrogels are networks of hydrated, cross-linked polymers which are powerful models of the extracellular matrix often used in cell biology; therefore they provide a promising substrate to study cancer biology. The ability to incorporate cell adhesive and protease degradable sequences, and growth factors with defined localisations and densities while controlling the pore size and mechanical properties of the substrate is a strong advantage over natural 3D systems which are difficult to define.

Since the tumour microenvironment is 3D and complex, we will engineer 3D hydrogels with controlled properties such as matrix stiffness, integrin binding sites and bound growth factors. These parameters will be varied systematically and a panel of pancreatic cancer cells will be analysed for their ability to migrate in 3D, and detailed imaging of the stroma and invading cells will be performed. We aim to gain insight into which properties of the matrix promote the spread of pancreatic cancer with the hope of targeting these for future therapies.