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

Abstract

SummaryChordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression and genomic variants associated with colorectal cancer (CRC) risk. BMP signalling in the normal intestinal epithelium operates in opposition to the WNT signalling pathway, which maintains stem-cells and self-renewal. Elevated WNT signalling leads to expansion of the stem cell compartment and hyperproliferation, defining characteristics of CRC.Here, we explored the impact of CHRDL2 overexpression on CRC cells and normal intestinal organoids to investigate whether CHRDL2’s inhibition of BMP signalling intensified WNT signalling, and enhanced the cancer stem-cell phenotype.CHRDL2 increased cell survival during chemotherapy and irradiation with associated activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem cell markers and reduced differentiation. RNA-seq analysis revealed that CHRDL2 increased the expression of stem cell markers and well-established cancer-associated pathways. We suggest that CHRDL2 overexpression can augment the stem-cell potential of CRC and normal intestinal cells.Graphical abstract