Identification of a Nervous System Gene Expression Signature in Colon Cancer Stem Cells Reveals a Role for Neural Crest RegulatorsEGR2andSOX2in Tumorigenesis

Abstract

SUMMARYRecent data support a hierarchical model of colon cancer driven by a population of cancer stem cells (CSCs). Greater understanding of the mechanisms that regulate CSCs may therefore lead to more effective treatments. Serial limiting dilution xenotransplantation assays of colon cancer patient-derived tumors demonstrated ALDHPositivecells to be enriched for tumorigenic self-renewing CSCs. In order to identify CSC modulators, we performed RNA-sequencing analysis of ALDHPositiveCSCs from a panel of colon cancer patient-derived organoids (PDOs) and xenografts (PDXs). These studies demonstrated CSCs to be enriched for embryonic and neural development gene sets. Functional analyses of genes differentially expressed in both ALDHPositivePDO and PDX CSCs demonstrated the neural crest stem cell (NCSC) regulator and wound response geneEGR2to be required for CSC tumorigenicity and to control expression of homeobox superfamily embryonic master transcriptional regulatorHOXgenes and the embryonic and neural stem cell regulatorSOX2. In addition, we identifyEGR2,HOXA2,HOXA4,HOXA5,HOXA7,HOXB2,HOXB3and the tumor suppressorATOH1as new prognostic biomarkers in colorectal cancer.