Research

In collaboration with Hans Clevers’ Laboratory, we have developed an organoid culture system that allows us to propagate benign and malignant pancreas tissue (Boj et al. 2014). Organoids are three-dimensional cultures of cells that propagate inside of an extracellular matrix and self-assemble into structures that mimic tissue architecture in vivo. Organoids can be generated from pancreatic tumors isolated from humans or mice, and are amenable to biochemical and genetic manipulation, allowing us to probe pancreatic cancer biology in the culture dish. Our human organoids serve as a genetically diverse collection of models for studying pancreatic cancer.

We have now amassed a large and diverse collection of human pancreatic tumor organoid models from which we have generated genome and transcriptome data. We can test the efficacy of potential cancer therapies on these organoids, and identify organoids that respond or are resistant to different therapies. By comparing our genetic and transcriptome data with the results of our therapeutic testing, we are working to identify molecular signatures that correlate with treatment response. Along those lines, we recently identified a gene expression signature predictive of organoid sensitivity to chemotherapy. We are now refining this signature, and developing it for use in the clinic. We are applying similar methodology to study organoid response to targeted agents.

To determine the extent of inter-patient and intra-patient heterogeneity, we have initiated a project with multiple sites internationally to collect and characterize 300 human organoids.  Single cell analyses will be performed on some of these specimens to determine the pattern of co-occurring mutations that define distinct genetic subtypes and likely represent unique therapeutic vulnerabilities. Isolation of the individual clones can be achieved as single cells can give rise to organoids.