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

• Published in: eLife 2024-11, Vol.13
• Main Authors: Shin, Jae Hun, Park, Jooyoung, Lim, Jaechul, Jeong, Jaekwang, Dinesh, Ravi K, Maher, Stephen E, Kim, Jeonghyun, Park, Soyeon, Hong, Jun Young, Wysolmerski, John, Choi, Jungmin, Bothwell, Alfred L M
• Format: Article
• Language: English
• Subjects: Ablation; Animals; Cancer Biology; Cancer cells; Cell differentiation; Cell Line, Tumor; Chromatin; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Development and progression; DKK2; Gene expression; Gene Expression Regulation, Neoplastic; Glucose; Glucose metabolism; Glycolysis; Health aspects; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes; Humans; Immunoprecipitation; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - secondary; Lysozyme; Metabolism; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Mortality; Mutation; Neoplasm Metastasis; Organoids; Paneth cell properties; Paneth cells; Paneth Cells - metabolism; Phosphorylation; Proteins; RNA; RNA sequencing; Scientific equipment and supplies industry; Sequence analysis; Sox9 protein; SOX9 Transcription Factor; Stem cells; Transcriptomes; Tumors; United States
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.97279

Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of , a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.