IBCN 2022: Spatial Prioritization of Cellular Interactions in the Tumor Microenvironment

(UroToday.com) a keynote lecture, Dr. Andreas Moor outlined his study using human samples and mice models to understand which cellular interactions a the interface between hepatocytes and metastatic colorectal cancer that would provide a supportive environment for metastasis. First, using array-based spatial transcriptomics on liver metastases samples collected from patients with colorectal cancer, gene expression on the junctional hepatocytes was examined. The highly expressed ligand-receptor pairs were then validated using multiplexed FISH analyses.

 

The group hypothesized that there are three fates related to cancer cells that intravasate into the blood stream and eventually extravasate to the liver: metastatic outgrowth into a growth promoting niche; clearance by the immune system; or remain dormant within the metastatic site. Using an in-vivo “outside-in” CRISPR screen, various ligand receptors pairs found to be highly expressed in the transcriptomic assays were sequentially tested in a mouse model to see which one would result in metastatic outgrowth. Using a Sleeping Beauty transposase model and a Cas9 system, the group can stably transduce 300 genes using 1000 guides in hepatocytes within a single mouse, forming a “mosaic liver”. In such animals, they then can use colorectal cancer cells to identify genes critically expressed in the proximal hepatocytes that would promote metastatic outgrowth. Finally, using colorectal cancer organoids with specific loss of function cognate ligands, the importance of the specific ligand-receptor pairs can be validated in vivo.

In conclusion, Dr. Moor pointed out the feasibility of spatial transcriptomic analysis that can aid in the selection of putatively relevant ligand-receptor interactions and the establishment of in vivo CRISPR activation-based proximity screen to test the functional relevance of these interactions. He theorizes that this model is easily adaptable to screen for interactions with other cell types in the tumor microenvironment.

 

Presented by: Andreas Moor, MD, PhD, Prof Andreas Moor is an assistant professor in the Department of Biosystems Science and Engineering (D-BSSE) at ETH Zurich

Written by: Roger Li, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain