Dickkopf-2 Promotes the Generation of Colon Cancer Cells with Paneth Cell Properties to Drive Metastasis

Core Concepts

Dickkopf-2 (DKK2) is essential for the generation of colon cancer cells exhibiting Paneth cell properties, which form a cancer stem cell niche to facilitate metastatic tumor growth.

Abstract

The content explores the role of Dickkopf-2 (DKK2) in the development of colon cancer metastasis. Key highlights: Splenic injection of Dkk2-knockout (KO) colon cancer organoids into mice resulted in significantly reduced liver metastases compared to control organoids. Transcriptome analysis showed a reduction of Paneth cell markers, such as lysozymes, in the Dkk2 KO organoids. Single-cell RNA sequencing of murine and human metastatic colon cancer samples identified the presence of lysozyme-positive (LYZ+) cancer cells with Paneth cell properties, including enhanced glycolysis. Mechanistically, DKK2 promotes the generation of LYZ+ cancer cells with Paneth cell characteristics by reducing the HNF4α1 protein level, which in turn enhances the expression of the Paneth cell transcription factor Sox9. The loss of LYZ+ cancer cells with Paneth cell properties in Dkk2 KO organoids and metastatic tumors resulted in reduced glycolysis and impaired metastatic growth, suggesting the importance of these cells in forming a cancer stem cell niche. Overall, the findings demonstrate that DKK2-mediated generation of colon cancer cells with Paneth cell properties is essential for the development of metastases.

Stats

Dkk2 knockout significantly reduced the percentage of lysozyme-positive (LYZ+) cancer cells in liver metastatic tumors compared to control. The percentile of LYZ+ cells in total cancer cells was decreased about 3-fold in Dkk2 knockout metastasized cells compared to the control.

Quotes

"DKK2 is indispensable for the generation of LYZ+ cancer cells in liver metastasized nodules by reducing protein levels of HNF4α1." "DKK2-driven loss of HNF4α1 protein enhances Sox9 expression in colon cancer cells to generate LYZ+ cells with Paneth cell properties."

Key Insights Distilled From

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

by Shin,J. H., ... at www.biorxiv.org 04-15-2024

https://www.biorxiv.org/content/10.1101/2024.04.12.589235v1

Deeper Inquiries

How do the Paneth cell-like properties of the LYZ+ colon cancer cells specifically contribute to the formation of the cancer stem cell niche and facilitate metastatic outgrowth?

The Paneth cell-like properties of the LYZ+ colon cancer cells play a crucial role in the formation of the cancer stem cell niche and the facilitation of metastatic outgrowth. Paneth cells are known to provide stem cell niche factors in the homeostatic condition, regulating the proliferation and differentiation of stem cells. In the context of colon cancer, the LYZ+ cancer cells exhibiting Paneth cell properties, such as enhanced glycolysis, contribute to the maintenance and generation of cancer stem cells within the tumor microenvironment. These LYZ+ cells provide metabolic support for stem cells, promoting their survival and proliferation. The presence of LYZ+ cells with Paneth cell characteristics ensures the availability of essential niche factors, including Wnt3, EGF, and Notch ligands, which are crucial for regulating stem cell behavior. By mimicking the functions of Paneth cells, the LYZ+ cancer cells create a microenvironment conducive to the maintenance and expansion of cancer stem cells. This niche formation is essential for the outgrowth of metastasized colon cancer cells, as it provides the necessary support for the survival and self-renewal of cancer stem cells during the metastatic process.

How do the Paneth cell-like properties of the LYZ+ colon cancer cells specifically contribute to the formation of the cancer stem cell niche and facilitate metastatic outgrowth?

The Paneth cell-like properties of the LYZ+ colon cancer cells specifically contribute to the formation of the cancer stem cell niche and facilitate metastatic outgrowth through several mechanisms: Regulation of Stem Cell Behavior: LYZ+ cells provide stem cell niche factors, such as Wnt3, EGF, and Notch ligands, which regulate the behavior of cancer stem cells. These factors promote stem cell proliferation and differentiation, contributing to the maintenance of the stem cell pool within the tumor. Metabolic Support: The enhanced glycolysis observed in LYZ+ cells is essential for providing metabolic support to cancer stem cells. By metabolically supporting stem cells, LYZ+ cells ensure their survival and proliferation, crucial for the formation of the cancer stem cell niche. Niche Formation: The presence of LYZ+ cells with Paneth cell properties creates a niche environment that mimics the physiological stem cell niche in the intestine. This niche provides a supportive microenvironment for cancer stem cells, promoting their self-renewal and maintenance. Overall, the Paneth cell-like properties of LYZ+ colon cancer cells play a pivotal role in establishing a conducive microenvironment for cancer stem cells, facilitating their survival, proliferation, and ultimately, metastatic outgrowth.

How do the Paneth cell-like properties of the LYZ+ colon cancer cells specifically contribute to the formation of the cancer stem cell niche and facilitate metastatic outgrowth?

The Paneth cell-like properties of the LYZ+ colon cancer cells contribute significantly to the formation of the cancer stem cell niche and the facilitation of metastatic outgrowth. These properties play a crucial role in creating a microenvironment that supports the survival, self-renewal, and proliferation of cancer stem cells, ultimately promoting metastasis. The LYZ+ cells exhibit characteristics similar to Paneth cells, providing essential stem cell niche factors such as Wnt3, EGF, and Notch ligands. These factors regulate stem cell behavior, including proliferation and differentiation, creating a supportive niche for cancer stem cells. Additionally, the enhanced glycolysis observed in LYZ+ cells provides metabolic support to stem cells, promoting their survival and growth within the tumor microenvironment. By mimicking the functions of Paneth cells, the LYZ+ colon cancer cells establish a niche that fosters the maintenance and expansion of cancer stem cells. This niche formation is critical for the outgrowth of metastatic colon cancer cells, as it creates a supportive environment for the progression of the disease. Targeting the DKK2-mediated generation of Paneth cell-like cancer cells could be a promising therapeutic strategy to disrupt the cancer stem cell niche and inhibit metastatic spread in colon cancer. This approach may involve inhibiting DKK2 signaling or targeting downstream pathways involved in the formation of LYZ+ cells, potentially leading to novel treatment options for preventing or treating colon cancer metastasis.