The Cell of Origin Defines the Transcriptional Program of APC-Transformed Organoids

In many cancers, tumorigenesis is determined in part by the cell type in the tissue that transforms, which has been called the cell of origin. In intestinal cancer, previous observations suggested that transformation can occur from both stem cells and more differentiated cells; in the latter case, this is provided that NF-kB is activated and apoptosis is blocked. However, whether these distinct transformation trajectories yield similar types of cancer remains unresolved. In this study the effect of APC loss within different cellular backgrounds was analyzed. Transformation of either stem-like cells or secretory-like cells, as defined by CD24 or c-KIT expression, by deleting the APC function in organoids in vitro, led to WNT-independent growth of organoids in both cellular populations. Importantly, transformed cultures derived from secretory-like cells had significantly distinct gene expression profiles as compared to the more stem cell-derived (CD44high cells) APC mutant cultures and in fact preserved a level of gene expression that relates back to their original cell lineage. Our data highlights the influence of different cellular backgrounds on the initiation of intestinal cancer and suggests that the cell of origin could be a defining factor in colorectal cancer heterogeneity.