Introduction
Pancreatic cancer is the most lethal of all solid malignancies. Patients are often diagnosed with progressive disease and treated with palliative intent. Most patients succumb to the disease within 6 months, with an average 5-year survival rate of 5-7%. These abysmal statistics highlight the urgent need to better understand the progression of pancreatic cancer so that novel treatment options can be identified.
Methods
An organoid and patient derived xenograft (PDX) pipeline has been optimised for the growth of either mouse or human pancreatic ductal adenocarcinomas (PDAC). Mouse organoids were generated from YFP+ ductal epithelial cells isolated from the primary tumour and matched liver metastases of the Pdx1-Cre;LSL-KrasG12D/+; LSL-p53R172H/+; LSL-YFPmouse model of PDAC, and successfully grown as syngeneic xenografts. Human PDAC organoids were derived from tissue collected at the time of surgical resection or cells obtained from fine needle aspirations, and successfully grown as PDXs. Together, these model systems provide a platform for characterisation of the behaviour of ductal epithelial cells, as well as for future pre-clinical drug trials.
Results and Conclusions
We have established a complementary suite of model systems that accurately recapitulate the histopathological and genetic features of PDAC. The organoid platform will provide a 3D culture system to directly examine epithelial cell behaviour, while the corresponding xenografts will allow for interrogation of stromal-epithelial interactions, an essential component of studying drug response in this desmoplastic disease. Together, these models will assist us in gaining a better understanding of PDAC progression, and hence, guide the discovery of new therapeutic opportunities.