Exploiting tumour-stromal interactions for pancreatic cancer therapy
There's more to tumours than cancer cells.
The development of all cancers is shaped by complex interactions between tumour cells and surrounding stromal cells. Stromal cells are normally responsible for the tightly regulated maintenance of connective tissue integrity but their critical role in cancer is now increasingly appreciated.
Pancreatic adenocarcinoma, among the most aggressive and rapidly fatal of all human cancers, is characterised by an unusually intense fibrotic reaction that results from abnormal tumour-stromal cell interactions: a phenomenon known as desmoplasia. Modulating interactions between neoplastic cells and stromal cells is an exciting new strategy that may offer an opportunity to slow or even prevent the development of cancer, as well as reducing the impact of established tumours. However, before new treatments can be developed, we need to increase our understanding of tumour-stromal interaction.
The principal objective of this research programme is to characterise and target abnormal tumour-stromal cell interactions that drive pancreatic cancer with a view to developing new approaches that may:
- Slow or reverse the progression of early premaligant disease to cancer
- Improve response rates to existing anti-cancer therapies
Prevention of cancer is likely to have the greatest impact on clinical outcomes. The development of many malignancies is marked by progression through a pre-invasive phase and current evidence favours a model in which pre-invasive lesions (pancreatic intraepithelial neoplasia, PanIN) develop into cancer. Tumour-stromal cell interactions appear to influence PanIN progression. If PanIN can be retarded or reversed at an early stage, pancreatic cancer might be averted.
Desmoplasia and therapeutic resistance
Once pancreatic cancer is established, the only potential for cure is surgical resection. Unfortunately only about 15% of patients have resectable disease. Chemotherapy may help some patients but levels of intrinsic and acquired resistance to current agents are extremely high. Desmoplasia forms a barrier to chemotherapeutic drug delivery and results in an environment rich in pro-inflammatory mediators that enhances cancer progression and chemoresistance. Targeting desmoplasia may improve drug delivery and enhance the efficacy of currently ineffective chemotherapeutic.
Modelling pancreatic disease
The group is using in vitro 3-D ‘organotypic’ culture models populated with patient-derived tumour and stromal cells that appear more faithfully to recapitulate the tumour microenvironment than standard 2-D cell culture systems. These models allow specific cell-cell interactions to be interrogated and manipulated. It is hoped that modelling tumour stromal cell interations in this way will inform the rational development of new individualised therapeutic approaches. Evaluating new agents in these model systems is expected to yield data more likely to reflect clinical responses.