Dysadherin/CA9 Axis Supports Colorectal Cancer Cell Survival and Aggressiveness in the Acidic Tumor Microenvironment

Abstract

Purpose: The tumor microenvironment (TME) controls how cancer progresses. Dysadherin is a cell membrane glycoprotein that is linked to the aggressive behavior of colorectal cancer (CRC). In this study, we looked into the potential relationship between dysadherin and tumor microenvironment. Methods: To get mechanistic insight, we performed bioinformatics analysis to discover the downstream signaling pathway of dysadherin using gene expression data of dysadherin knock-out CRC cells. Moreover, we investigated the effect of dysadherin and downstream molecules using CRC patient samples, CRC cell lines, and mouse model. Results: The result of the bioinformatic analysis revealed that dysadherin depletion is linked to lactate metabolism, acidosis, and metastasis. Mechanistically, we identified carbonic anhydrase IX (CA9), which provides an advantage to cancer cells by preventing over-acidification-induced cell death. Consistent with the discovered mechanism, dysadherin/CA9 axis boosted survival and metastasis potential under the acidic TME, according to the pathological and functional investigation. Conclusion: Our results revealed a novel mechanism of dysadherin that promotes CRC progression in acidic TME, providing a potential therapy strategy for CRC.