5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation

Yong-Hee Cho, Eun Ji Ro, Jeong-Su Yoon, Tomohiro Mizutani, Dong-Woo Kang, Jong-Chan Park, Tae Kim, Hans Clevers and Kang-Yell Choi ()
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Yong-Hee Cho: College of Life Science and Biotechnology, Yonsei University
Eun Ji Ro: College of Life Science and Biotechnology, Yonsei University
Jeong-Su Yoon: College of Life Science and Biotechnology, Yonsei University
Tomohiro Mizutani: Cancer Genomics Netherlands, UMC Utrecht
Dong-Woo Kang: Medpacto Bio Institute, Medpacto Inc
Jong-Chan Park: College of Life Science and Biotechnology, Yonsei University
Tae Kim: Yonsei University College of Medicine
Hans Clevers: Cancer Genomics Netherlands, UMC Utrecht
Kang-Yell Choi: College of Life Science and Biotechnology, Yonsei University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.

Date: 2020
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DOI: 10.1038/s41467-020-19173-2

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