Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

Sep 21, 2026

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Metastasis is the leading cause of cancer-related mortality. Paneth cells supply stem-cell niche factors under homeostatic conditions, but how cancer stem-cell niche development is established during metastasis remains unclear. This study reports that Dickkopf-2 (DKK2) is essential for generating cancer cells with Paneth cell properties during colon cancer metastasis. Functional assays show reduced lysozyme-positive cells and metastasis-associated changes when DKK2 is disrupted, alongside a DKK2→HNF4A→Sox9 regulatory pathway.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

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Introduction

Metastasis and Wnt signaling in colorectal cancer

Lgr5+ cells, stem cell niches, and Paneth cell functions

Abstract

RESEARCH ARTICLE *For correspondence: [jaehun.shin@yonsei.ac.kr](jaehun.shin@yonsei.ac.kr)[ ](jaehun.shin@yonsei.ac.kr)(JHunS); [albothwell@unmc.edu](albothwell@unmc.edu) (ALMB) Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties Jae Hun Shin1,2*†, Jooyoung Park3†, Jaechul Lim4, Jaekwang Jeong5, Ravi K Dinesh6, Stephen E Maher7, Jeonghyun Kim2, Soyeon Park2, Jun Young Hong8, John Wysolmerski5, Jungmin Choi3, Alfred LM Bothwell9,10* 1 Integrative Science and Engineering Division, Underwood International College, Yonsei University, Incheon, Republic of Korea; 2 Institute of Advanced Bio-Industry Convergence, Yonsei University, Seoul, Republic of Korea; 3 Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea; 4College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea; 5 Internal Medicine, Yale University School of Medicine, New Haven, United States; 6 Department of Pathology, Stanford University, Stanford, United States; 7 Department of Urology, Yale University School of Medicine, New Haven, United States; 8 Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea; 9 Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, United States; 10 Department of Immunobiology, Yale University School of Medicine, New Haven, United States †These authors contributed ~~ ~~ equally to this work Competing interest: See page eLife Assessment 17 This valuable study proposes that protein secreted by colon cancer cells induces cells with PanethFunding: See page 17 like properties that favor colon cancer metastasis. The evidence supporting the conclusions is solid Sent for Review but the study would benefit from more direct experiments to test the functional role of Paneth- 12 April 2024 like cells and to monitor metastasis from colon tumors. The work will be of interest to researchers Preprint posted studying colon cancer metastasis. 15 April 2024 ~~ ~~ Reviewed preprint posted 0RJviuneewe2d02peprint revised Abstract Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem 22 October 2024 cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell Version of Record published niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the gener- 13 November 2024 ation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of RFCienavnl,rMinCgeeEmntrrii,oUl rSn:liLyoateiaKSWetattSteesring lieKrOmeotrasgatnasoiss.. TSrianngslcer-iptcelol me aRNAnsaelyqsuis seniowngeareducalysestoiofnmriPnaenetmtceastlal msiazerkdecrsolsouncaanscelyrsozymcellses and patient samples identified the presence of lysozyme positive cells with Paneth cell proper- Copyright Shin, Park et al. ties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility This article is distributed under suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2 . Chromatin the terms of the Creative immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter Commons Attribution License, which permits unrestricted use region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metaand redistribution provided that static foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive the original author and source cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation are credited. of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers. Shin, Park et al. eLife 2024;13:RP97279. DO

FAQs

What is the central finding about Dickkopf-2 in colon cancer metastasis?

Dickkopf-2 (DKK2) is essential for generating cancer cells that acquire Paneth cell properties during colon cancer metastasis.

How does DKK2 disruption affect metastasis-associated cancer cell features?

Loss of Dkk2 (including knockout models) significantly reduces the generation of lysozyme-positive cancer cells with Paneth-like properties in metastatic settings.

Which downstream pathway is implicated in DKK2-driven Paneth-like differentiation?

The study identifies hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2, with HNF4A binding to the Sox9 promoter to support Paneth cell differentiation.

Sep 21, 2026

Upload by Quinn