Prox1 Promotes Expansion of the Colorectal Cancer Stem Cell Population to Fuel Tumor Growth and Ischemia Resistance

Colorectal cancer (CRC) initiation and growth is often attributed to stem cells, yet little is known about the regulation of these cells. We show here that a subpopulation of Prox1-transcription-factor-expressing cells 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 via induction of annexin A1 and reduction of the actin-binding protein filamin A, which has been implicated as a prognostic marker in CRC. 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. [Display omitted] •Prox1 expression is dispensable for homeostasis in the normal intestine•A subpopulation of Prox1+ cells has stem cell activity in intestinal adenomas/CRC•Loss of Prox1 decreases adenoma/CRC stem cells, tumor cell growth, and survival•Annexin A1 and filamin A mediate Prox1 effects on stem cell activity in the tumors Wiener et al. now show that the Prox1 transcription factor functions as a stem cell regulator in intestinal adenomas and colorectal cancer (CRC), but not in the normal intestine. Prox1 critically contributes to tumor cell survival in hypoxia and to the expansion of the adenoma/CRC stem cell population via inhibition of the Wnt-target annexin A1 and induction of the actin-binding protein filamin A. The Prox1 pathway thus represents an attractive therapeutic target for drug development in CRC.