Slow-Cycling Cancer Stem Cells Regulate Progression and Chemoresistance in Colon Cancer.

Abstract

Cancer chemoresistance is often attributed to the presence of cancer stem cell (CSC)-like cells, but whether they are homogeneously chemoresistant remains unclear. We previously showed that in colon tumors, a subpopulation of <i>LGR5⁺</i> CSC-like cells driven by TCF1 (TCF7), a Wnt-responsive transcription factor, were responsible for tumorigenicity. Here we demonstrate that the tumorigenic subpopulation of mouse <i>LGR5⁺</i> cells exists in a slow-cycling state and identify a unique 22-gene signature that characterizes these slow-cycling CSC. Seven of the signature genes are specifically expressed in slow-cycling <i>LGR5⁺</i> cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (<i>APCDD1, NOTUM, PROX1</i>, and <i>SP5</i>) are known to be direct Wnt target genes, and <i>PROX1</i> was expressed in the invasive fronts of colon tumors. <i>PROX1</i> was activated by TCF1 to induce CDKN1C and maintain a slow-cycling state in colon cancer organoids. Strikingly, PROX1 was required for recurrent growth after chemotherapeutic treatment, suggesting that inhibition of slow-cycling CSC by targeting the TCF1-PROX1-CDKN1C pathway is an effective strategy to combat refractory colon cancer in combination with conventional chemotherapy. SIGNIFICANCE: These findings illustrate the importance of a slow-cycling CSC subpopulation in colon cancer development and chemoresistance, with potential implications for the identified slow-cycling CSC signatures and the TCF1-PROX1-CDKN1C pathway as therapeutic targets.