CHRDL2, a BMP Antagonist, Enhances Cancer Stem Cell Characteristics and Chemotherapy Resistance in Colorectal Cancer

Core Concepts

CHRDL2 overexpression in colorectal cancer cells enhances stem-like characteristics, including increased expression of stem cell markers, decreased differentiation, and elevated resistance to chemotherapy and radiation treatment.

Abstract

The study investigates the functional role of CHRDL2, a secreted BMP antagonist, in colorectal cancer (CRC). CHRDL2 has been previously linked to poor prognosis and increased CRC risk, but its precise effects were unknown.
The researchers used CRC cell lines engineered to inducibly overexpress CHRDL2 and 3D intestinal organoid models treated with secreted CHRDL2 to explore the impact on cancer stem cell properties and treatment response.
Key findings:

CHRDL2 overexpression decreased proliferation and clonogenicity of CRC cells, but enhanced their migratory ability.
CHRDL2 significantly increased resistance to common CRC chemotherapies (5-FU, irinotecan, oxaliplatin) and radiation treatment.
Mechanistically, CHRDL2 overexpression reduced DNA damage during chemotherapy by upregulating DNA repair pathways.
In intestinal organoids, secreted CHRDL2 decreased differentiation, increased expression of stem cell markers (OLFM4, LGR5, BMI1), and enhanced the stem-like phenotype.
RNA-seq analysis revealed CHRDL2 upregulated WNT signaling, stem cell pathways, and other cancer-associated pathways.
These findings suggest that CHRDL2 overexpression enhances the cancer stem cell phenotype in CRC, potentially impacting treatment response and prognosis. CHRDL2 should be further explored as a biomarker and therapeutic target in CRC.

Stats

"CHRDL2 overexpression significantly increased resistance to chemotherapy in all cell lines (P<0.01) as shown by elevated IC50 values."
"CHRDL2 overexpression resulted in an approximate twofold increase in IC50 values compared to control cells, (P<0.001)."
"The greatest increase in survival (exhibited by ratios of IC50s) was seen in COLO320 cells treated with oxaliplatin, which had a 3.6 fold increase."
"CHRDL2 overexpression increased cell survival at 4GY and 6GY radiation (P<0.03, P<0.02,)."
"CHRDL2 overexpressing cells had significantly fewer γH2AX foci compared to the control at each time point (P<0.01)."
"CHRDL2 overexpression significantly increased the expression of stem-cell markers LGR5 (P<0.04), BMI1 (P<0.0113), and SOX9 (P<0.0014) in organoids."

Quotes

"CHRDL2 overexpression significantly increased resistance to chemotherapy in all cell lines (P<0.01) as shown by elevated IC50 values."
"CHRDL2 overexpression resulted in an approximate twofold increase in IC50 values compared to control cells, (P<0.001)."
"CHRDL2 overexpressing cells had significantly fewer γH2AX foci compared to the control at each time point (P<0.01)."

Key Insights Distilled From

BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in Colorectal Cancer

by Clarkson,E.,... at www.biorxiv.org 01-26-2024

https://www.biorxiv.org/content/10.1101/2024.01.23.576664v2

Deeper Inquiries

How could the insights from this study on CHRDL2's role in enhancing cancer stem cell properties be leveraged to develop more effective combination therapies for colorectal cancer

The insights from this study on CHRDL2's role in enhancing cancer stem cell properties can be leveraged to develop more effective combination therapies for colorectal cancer by targeting the specific pathways affected by CHRDL2. Since CHRDL2 inhibits BMP signaling and intensifies WNT signaling, therapies that target these pathways could be combined with traditional chemotherapy to improve treatment outcomes. For example, combining CHRDL2 inhibitors with standard chemotherapy drugs like 5-Fluorouracil, Irinotecan, and Oxaliplatin could potentially overcome the resistance seen in cancer stem cells. Additionally, targeting downstream pathways activated by CHRDL2, such as MYC, MTOR, and RAF, could provide new avenues for combination therapies. By understanding the molecular mechanisms underlying CHRDL2's effects, researchers can design more targeted and personalized treatment strategies for colorectal cancer patients.

What other BMP antagonists, besides CHRDL2, might play a similar role in modulating stem-like characteristics and treatment resistance in colorectal cancer, and how do their mechanisms compare

Other BMP antagonists that might play a similar role in modulating stem-like characteristics and treatment resistance in colorectal cancer include Noggin and Gremlin (GREM1 and GREM2). Noggin, like CHRDL2, inhibits BMP signaling and has been implicated in promoting tumorigenesis in various cancers. Gremlin proteins, especially GREM1, have been shown to enhance stem-like properties in intestinal epithelial cells and promote tumorigenesis. The mechanisms of action of these BMP antagonists are similar to CHRDL2, involving the inhibition of BMP signaling and the promotion of WNT signaling, leading to increased stem cell characteristics and treatment resistance. By targeting these BMP antagonists and their downstream pathways, researchers can develop novel therapeutic strategies to overcome treatment resistance in colorectal cancer.

Given the complex and context-dependent effects of BMP signaling in cancer, how might a deeper understanding of the interplay between BMP, WNT, and other key pathways regulated by CHRDL2 inform the development of more personalized treatment approaches for colorectal cancer patients

A deeper understanding of the interplay between BMP, WNT, and other key pathways regulated by CHRDL2 can inform the development of more personalized treatment approaches for colorectal cancer patients by identifying specific molecular targets for therapy. By elucidating the crosstalk between BMP and WNT signaling pathways, researchers can identify potential biomarkers for patient stratification and predict treatment responses. Understanding how CHRDL2 modulates these pathways can help in the development of targeted therapies that specifically inhibit or activate key molecules involved in cancer stem cell maintenance and treatment resistance. This knowledge can also guide the development of combination therapies that target multiple pathways simultaneously, leading to more effective and personalized treatment options for colorectal cancer patients.