한빛사 논문
Yong-Hee Cho1,6, Eun Ji Ro1,6, Jeong-Su Yoon1, Tomohiro Mizutani2, Dong-Woo Kang3, Jong-Chan Park1, Tae Il Kim4, Hans Clevers2 & Kang-Yell Choi1,5,*
1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea. 2Hubrecht Institute, Cancer Genomics Netherlands, UMC Utrecht, 3584CT Utrecht, Netherlands. 3Medpacto Bio Institute, Medpacto Inc, Seoul 06668, Republic of Korea. 4Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. 5CK Biotechnology Inc, Yonsei Engineering Complex B137A, 50 Yonsei Ro, Seodaemun-Gu, Seoul 03722, Korea. 6These authors contributed equally: Yong-Hee Cho, Eun Ji Ro.
*Corresponding author
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.
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