The English sea captain and politician Sir Francis Drake believed in “sic parvis magna”, or “greatness from small beginnings”. While he hasn’t been around to see the recent explosion in organoid (or mini-organ) research, we are sure he would be impressed.
Measuring a few millimeters in diameter and produced via three-dimensional differentiation of stem cells, organoids have helped us to model development and disease (including autism) and may even allow the production of patient-specific transplantable organs (including the kidneys).
Researchers from the laboratories of Nancy A Jenkins and Michael L Shuler realized the potential of organoids towards their research into colon cancer, but they encountered a small problem. Intestinal organoid systems currently described in the literature (Lu et al, Matano et al, and Jung et al) lack native tissue structures and extracellular matrix (ECM) components, meaning they cannot mimic vital aspects of intestinal physiology.
To solve this problem, the team took human colon samples, removed all the cells, and then repopulated the 3D tissue/ECM “skeleton” with replacement cells carrying specific gene mutations, so creating a new kind of organoid model to study. Sounds like a great tool for colon cancer research! So how did it go?
- The authors reseeded a section of decellularized colon skeleton with human colonic epithelial cells, endothelial cells, and myofibroblasts
- Epithelial cells carried mutations in colon cancer genes such as APC (linked to the initiation of cancer) and KRAS (linked to the development of early stage cancer)
- Inactivation of TGF-β signaling via inhibitor injection drove colon cancer progression
- Culture of the colon cancer organoid model quickly and faithfully recapitulated the progressive steps of colon cancer development, suggesting it to be a useful tool
- The authors then used this model to identify genes that work together with mutant APC to drive cancer invasiveness
- They used a Sleeping Beauty (SB) transposon mutagenesis screen as an unbiased, high-throughput tool for cancer gene candidate discovery
- 17 of 38 uncovered candidate genes had previously been linked to cancer progression
- The authors described and validated six novel colon cancer “enhancer” genes (ASXL2, CAMTA1, DDX20, FXR1, MITF, and PAX7)
This organoid model of colon cancer may find use as an intermediary between simple and easy two-dimensional monolayer cell assays and the expensive and complex animal studies to aid in the progress of colon cancer studies.
A small colon sample looks like it might lead to some great findings; Sir Francis Drake would approve. See more about this exciting new tool for cancer research at Nature Biotechnology, July 2016.