PROX1 is required for cancer stem cell expansion and metastatic outgrowth in colorectal cancer.
Major finding: PROX1 is required for cancer stem cell expansion and metastatic outgrowth in colorectal cancer.
Mechanism: PROX1 promotes stem cell proliferation, induces metabolic adaptation, and suppresses apoptosis.
Impact: Autophagy inhibition may limit PROX1+ cell growth and metastasis without affecting the normal gut.
The WNT pathway is a critical regulator of intestinal stem cells, and aberrant activation of WNT signaling is an early event that drives colorectal tumor initiation. However, the factors that regulate colorectal cancer stem cells and the contribution of these factors to metastatic progression remain poorly understood. Wiener, Högström, and colleagues found that Prospero homeobox 1 (PROX1), a transcription factor that is induced by WNT and has been implicated in colorectal cancer progression, was expressed in leucine-rich repeat containing G protein-coupled receptor 5–positive (LGR5+) stem cells in early intestinal adenomas following WNT activation, but not in normal intestinal stem cells. Depletion of PROX1 prevented expansion of LGR5+ stem cells in mouse adenomas and human colorectal cancer organoids, resulting in decreased cell proliferation and diminished growth of established colorectal cancer xenografts. PROX1-mediated maintenance of cancer stem cells was dependent on repression of annexin A1 and induction of the actin-binding protein filamin A. Consistent with these findings, Ragusa and colleagues found that PROX1 was highly expressed in colorectal cancer metastases, in particular in a subpopulation of stem/progenitor cells with elevated WNT activity, and was correlated with increased proliferation of metastatic cells. PROX1 was required for the clonogenic growth of colorectal cancer stem cells and was necessary and sufficient to promote metastatic outgrowth and maintenance of established metastatic lesions in an orthotopic model of WNT-driven colorectal cancer even in the presence of additional mutations. PROX1 enhanced tumor cell survival under hypoxia and nutrient deprivation by stimulating metabolic adaptation and suppressing apoptosis, in part through transcriptional repression of the proapoptotic gene BCL2L15. Intriguingly, both groups showed that PROX1-mediated tumor cell survival relied on autophagy; inhibition of autophagy with chloroquine resulted in loss of stem cells and preferentially suppressed the proliferation of PROX1+ metastases. Together, these findings identify the PROX1 pathway as a potential therapeutic target to limit growth and metastasis in colorectal cancer.
Wiener Z, Högström J, Hyvönen V, Band AM, Kallio P, Holopainen T, et al. Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Rep 2014;8:1943–56.