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

Abstract

BMP antagonists have been increasingly linked to the development of Colorectal cancer (CRC). BMP signalling operates in opposition to the WNT signalling pathway, which sustains stem-cell maintenance and self-renewal of the normal intestinal epithelium. Reduced BMP and elevated WNT signalling lead to expansion of the stem-cell compartment and the hyperproliferation of epithelial cells, a defining characteristic of CRC. Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression linked to poor prognosis and variants in the gene shown to be associated with an elevated CRC risk. Despite this the functional role of CHRDL2 in CRC is unknown. In this study, we explored the impact of CHRDL2 overexpression on CRC cells to investigate whether CHRDL2s inhibition of BMP signalling intensifies WNT signalling and enhances the cancer stem-cell phenotype and response to treatment. Our research approach combines 2D cancer cell lines engineered to inducibly overexpress CHRDL2 and 3D organoid models treated with extrinsic CHRDL2, complemented by RNA sequencing analysis. CHRDL2 was found to enhance the survival of CRC cells during chemotherapy and irradiation treatment due to activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem-cell markers and reduced differentiation, as evidenced by diminished villi budding. RNA-seq analysis revealed that CHRDL2 increased the expression of stem-cell markers, WNT signalling and other well-established cancer-associated pathways. These findings collectively suggest that CHRDL2 overexpression could affect response to CRC therapy by enhancing DNA repair and the stem-cell potential of cancer cells, and its role as a biomarker should be further explored. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/576664v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1465646org.highwire.dtl.DTLVardef@ca333forg.highwire.dtl.DTLVardef@ea8204org.highwire.dtl.DTLVardef@1fe0f8d_HPS_FORMAT_FIGEXP M_FIG C_FIG