![]() ![]() We are investigating the regulation of the intestinal stem cell (ISC) compartment by extracellular signals such as Wnts, using adenoviral and conditional knockout approaches. The complete regeneration of the epithelial lining of the intestine every 5-7 days renders the intestine a model system for studying stem cell behaviors. We are establishing proof-of-principle for human or mouse organoid transplantation, ultimately to effect phenotypic correction of diseases. We are also interested in using organoids as a method to grow mini-organs that can be transplanted into recipients for regenerative medicine purposes. ![]() Further, we have established large biobanks of organoids from clinical cancer biopsies with relevance to tumor modeling and predication of patient responses to therapeutics. In a new direction, we have developed organoid methods to preserve tumor cells along with a diversity of endogenous infiltrating immune cells (T, B, NK, macrophages) and demonstrated that such organoids are responsive to checkpoint inhibitor therapy (Neal et al, Cell 2018). These organoid systems comprise an robust in vitro system which we are exploiting for the functional validation of putative oncogenic loci which are identified in whole-genome cancer surveys such as TCGA. We have successfully established primary 3D organoid cultures of diverse tissues and used them to achieve the first in vitro conversion of primary intestine, stomach and pancreas tissue to adenocarcinoma (Ootani et al, Nat Med 2009 Li et al, Nat Med 2014) amongst others. Organoid modeling of cancer cells and the tumor immune microenvironment.
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