Abstract 2320: Prox1 marks a stem cell population that promotes tumor progression in intestinal adenomas

Abstract

Abstract Colorectal cancer (CRC) initiation and growth is often attributed to stem cells, yet little is known about the regulation of this cell population. We have shown that a subpopulation of cells expressing the Prox1 transcription factor have stem cell activity in intestinal adenomas, but not in the normal intestine. Using in vivo models and 3D ex vivo organoid cultures of mouse adenomas and human CRC, we found that Prox1 deletion reduced the number of stem cells and cell proliferation and decreased intestinal tumor growth in multiple CRC model systems. Loss of Prox1 also decreased autophagy and the survival of hypoxic tumor cells in tumor transplants. Thus, Prox1 is essential for the expansion of the stem cell pool in intestinal adenomas and CRC without being critical for the normal functions of the gut. To further study the adenoma stem cells in relation to the Prox1-positive cell population, we analyzed Apc-mutant intestinal organoids derived from Prox1-CreER; tdTomatoflox/Stop/flox; Apcmin/+ mice. In this lineage tracing model, the induction of Cre activity results in the expression of the red fluorescent protein tdTomato only in the Prox1-positive adenoma cells. FACS sorted tdTomato-positive cell population displayed a highly elevated capability to form new organoids compared to the tdTomato-negative cells, consistent with stem cells enrichment in the Prox1-positive cell population. Gene expression analysis provided new clues about the identity of the Prox1 positive cells. Citation Format: Zoltan Wiener, Jenny Högström, Ville Hyvönen, Pauliina Kallio, Sarika Heino, Kari Alitalo. Prox1 marks a stem cell population that promotes tumor progression in intestinal adenomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2320. doi:10.1158/1538-7445.AM2015-2320