Slow-cycling cancer stem cells regulate progression and chemoresistance in colon cancer

Daisuke Shiokawa, Hiroaki Sakai, Hirokazu Ohata, Toshiaki Miyazaki, Yusuke Kanda, Shigeki Sekine, Daichi Narushima, Masahito Hosokawa, Mamoru Kato, Yutaka Suzuki, Haruko Takeyama, Hideki Kambara, Hitoshi Nakagama, Koji Okamoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


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 LGR5þ 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 LGR5þ 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 LGR5þ cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (APCDD1, NOTUM, PROX1, and SP5) are known to be direct Wnt target genes, and PROX1 was expressed in the invasive fronts of colon tumors. PROX1 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.

Original languageEnglish
Pages (from-to)4451-4464
Number of pages14
JournalCancer Research
Issue number20
Publication statusPublished - 2021 Oct 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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