Understanding how tissue stiffening affects cancer cell response to therapy

点击翻译按钮获取中文摘要

Pancreatic cancer has a low survival rate and new therapies are urgently needed. Currently the only treatments available are chemotherapy drugs that non-specifically target DNA replication and cell cycle progression. However, a new class of small molecule inhibitors have recently been developed targeting KRAS, an oncogene mutated in 90% of pancreatic cancers, which offer new promise for targeted therapy. One of the reasons that pancreatic cancer is so hard to treat is that tumours are surrounded by extremely rigid, fibrotic extra-cellular matrix (ECM). This altered tumour microenvironment means that tumours are far stiffer than healthy tissue. Tissue stiffening has been shown to promote cancer cell proliferation, invasion and metastasis but also contribute to resistance to therapy.This 4-year PhD project will investigate how the stiffness of the extracellular environment affects pancreatic cancer cell response to therapy, including standard chemotherapy drugs and new KRAS inhibitors. We will use a variety of cell biology techniques including cell culture, RNA sequencing and cutting-edge microscopy to unpick the molecular details of cells response to therapy. To understand the effects of tissue stiffening, cells will be grown in micro-fabricated chambers where the stiffness and ECM composition can be varied and mechanical forces (such as compression) can be applied.This is a collaborative project between the Helen Matthews' (School of Biosciences) and Helen Bryant's (Dept. of Oncology and Metabolism) groups at the University of Sheffield. Being embedded within both the Biosciences and Oncology departments, this project will provide a broad training in cell and cancer biology and give access to a wide variety of development opportunities, in addition to those provided by the MRC DiMeN scheme. Both the Matthews and Bryant groups are based in shared laboratories that provide friendly, inclusive and supportive environments for our cancer researchers.