Characterizing cellular heterogeneity of colonic neoplasia

Abstract

Cancer is a heterogeneous disease displaying a variety of cell populations inter- and intra-tumorally. This heterogeneity poses a challenge to cancer treatment, as more heterogeneous cellular populations are more prone to therapy resistance and metastasize. Understanding heterogeneous cell behaviors are critical; yet, conventional bulk experimental approaches are inadequate for characterizing heterogeneous cells from tissues. Here we apply multiple single-cell technologies to probe cancer heterogeneity in humans and mice. Specifically, we improved upon our previously published Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue (DISSECT) technique by verifying the signals seen in (FFPE) murine and human tissues. We applied this technique tissue to explore the cellular heterogeneity within human colorectal cancer. Moreover, utilizing other single-cell technologies including single-cell RNA-seq and multiplexed imaging, we investigated the tumor make-up of non-stem and stem cell-driven colorectal tumors. We revealed reduced stem capacity but increased class II antigen presentation ability for non-stem cell-driven tumor stem cells (TSCs) compared with stem cell-driven TSCs, which resulted in a favorable immune microenvironment skewed towards active cytotoxic response in non-stem cell-driven tumors. These results suggest that the cell-of-origin of tumorigenesis provides a specific context by which TSCs are generated, dictating their interactions with the tumor microenvironment.