Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma

Abstract

Summary: Various populations of cancer stem cells (CSCs) have been identified in hepatocellular carcinoma (HCC). Wnt signaling is variably activated in HCC and regulates CSCs and tumorigenesis. We explored cell-to-cell Wnt and stemness heterogeneity in HCC by labeling freshly isolated cancer cells with a Wnt-specific reporter, thereby identifying a small subset (0.4%–8.9%) of Wnt-activityhigh cells. Further cellular subset analysis identified a refined subset of Wnt-activityhighALDH1+EpCAM+ triple-positive (TP) cells as the most stem-like, phenotypically plastic, and tumorigenic among all putative CSC populations. These TP “superpotent CSCs” (spCSCs) specifically upregulate the expression of dishevelled 1 (DVL1) through the antagonism between abnormal spindle-like microcephaly-associated (ASPM) and the ubiquitin ligase complex Cullin-3/KLHL-12. Subsequent functional and molecular studies revealed the role of DVL1 in controlling spCSCs and their tumorigenic potential. These findings provide the mechanistic basis of the Wnt and stemness heterogeneity in HCC and highlight the important role of DVL1high spCSCs in tumor progression. : In this article, Tsai and colleagues investigated the Wnt and stemness heterogeneity in HCC and identified a novel subset of Wnt-activityhigh “superpotent cancer stem cells” (spCSCs). The existence of spCSCs is independent of β-catenin mutations and its proportion correlates with poor prognosis in patients with HCC. Mechanistically, spCSCs are positively regulated by the Wnt-ASPM-DVL1 signaling axis through protein-protein interactions. Keywords: Dishevelled-1, Wnt, cancer stem cells, hepatocellular carcinoma, heterogeneity, ASPM, ubiquitin ligase, prognostic marker