Abstract 4637: Non-stem cell-driven colonic tumors retain an intestinal differentiation hierarchy

Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Cancer stem cells (CSCs) play critical roles in therapeutic resistance, tumor recurrence, and metastasis that lead to patient death. We propose to evaluate the properties of CSCs in the context of the tumor cell-of-origin, the cell that initiates oncogenesis. We hypothesize that the tumor cell-of-origin is directly related to the CSCs present in tumors that consequently arise. To test this hypothesis, the stem-like properties of CSCs from stem cell- and non-stem cell-driven tumors, initiated from the Lrig1 and Mist1 promoters, respectively, were analyzed and compared through the use of lineage mapping and single-cell RNA-sequencing. We observed that although Mist1-expressing non-stem cells do not exhibit stem cell behavior under homeostatic or damage conditions, they can serve as tumor cells-of-origin. These tumors maintain a differentiation hierarchy that is lacking in stem cell-driven tumors. These results suggest that the origin of tumorigenesis influences tumor CSCs and thus tumor characteristics which could be utilized for the development of novel therapies. Citation Format: Cherie R. Scurrah, Alan J. Simmons, Eunyoung Choi, Robert J. Coffey, James R. Goldenring, Ken S. Lau. Non-stem cell-driven colonic tumors retain an intestinal differentiation hierarchy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4637.