Pancreatic Cancer and Cell and Molecular Biology: Joint Pump-Priming Grant

We are very pleased to announce that the joint Pancreatic Cancer-Cell and Molecular Biology pump-priming grant has been awarded to Dr Giulia Biffi (Junior Group Leader, CRUK Cambridge Institute) and Dr Alessandro Esposito (MRC Senior Investigator Scientist, MRC Cancer Unit).

The joint pump-priming grant aims to encourage collaboration between the Pancreatic Cancer and Cell and Molecular Biology Programmes to address current issues in pancreatic cancer research, and will fund up to £50,000 over a period of approximately 18 months.

 

KRAS-dependent reprogramming of tumour-stromal heterogeneity in pancreatic ductal adenocarcinoma

Dr Giulia Biffi and Dr Alessandro Esposito

Only 1 in 10 patients with pancreatic cancer survives for at least five years after diagnosis largely due to the limited therapeutic options available to date. Compared to any other cancer type, pancreatic cancer is characterised by the highest presence (more than 9 in 10 tumours) of mutations in KRAS, a key tumour-driving protein. Also, the involvement of non-cancerous but tumour-promoting components, collectively called stroma, is very extensive in pancreatic cancer, making up to 90% of the tumour mass. Within the stroma, fibroblasts are the most abundant cell population and promote drug resistance and cancer growth. To date, effective targeting of fibroblasts and KRAS remains challenging.

We hypothesise that different KRAS mutations detected in pancreatic tumours trigger distinct biological processes. Therefore, we argue about the importance to characterise these differences to improve the effectiveness of treatment. To this end, we will integrate cutting-edge technologies to trigger with high spatiotemporal control diverse tumour-driving KRAS mutations in three-dimensional cultures that mimic pancreatic cancer tissues (pancreatic organoid/fibroblast co-cultures). We will then monitor in real-time the biochemical changes that lead to tumour formation and reprogramming of pancreatic fibroblasts.

Our work will identify mutant KRAS-dependent signalling mechanisms that occur at early and late stages of pancreatic cancer progression in both cancer cells and fibroblasts. These results could be used to design novel combination therapies, as distinct KRAS-dependent phenotypes likely play different roles in pancreatic cancer progression and targeting them selectively may lead to disparate outcomes. As KRAS mutations and fibroblast heterogeneity are not restricted to pancreatic cancer, our findings could have a broader impact in oncology.