Abstract 5111: Targeting the dysadherin/CA9 axis inhibits colorectal cancer adaptation and growth within the acidic tumor microenvironment

Abstract The tumor microenvironment (TME) has a significant impact on colorectal cancer (CRC) progression by promoting tumor survival and aggressive behavior. A key player in this process is the tumor-associated glycoprotein dysadherin, which is highly expressed in aggressive CRC cells and facilitates their adaptation to the TME. In this study, we conducted a comprehensive bioinformatics analysis of clinical genomic data from CRC patients, integrated with studies on dysadherin-knockout CRC cells. We also examined the downstream effects of dysadherin in human CRC cells, patient tissue samples, and a xenograft mouse model. Through bioinformatics and pathological analysis, we found that increased tumor acidity is a prominent feature of CRC progression and is positively associated with high dysadherin expression. Overexpression and silencing studies of dysadherin in CRC cells further confirmed that high dysadherin levels enhance malignant traits, especially under acidic conditions within the TME. Mechanistically, dysadherin activates the Integrin/FAK/STAT3 signaling pathway, leading to upregulation of carbonic anhydrase 9 (CA9). CA9 helps cancer cells survive in acidic environments by maintaining intracellular pH balance. By buffering the acidic TME, CA9 enhances CRC cell adaptation and resilience in an otherwise hostile environment. Notably, the deletion of dysadherin in xenograft models led to reduced tumor growth, while the reintroduction of CA9 restored malignancy, underscoring the essential role of the dysadherin/CA9 axis. This pathway is crucial for CRC cell survival in acidic TME, positioning dysadherin and CA9 as promising prognostic markers and therapeutic targets. Targeting this axis could disrupt CRC progression, offering new therapeutic avenues and potentially more effective interventions for inhibiting disease advancement Citation Format: Jeong-Seok Nam, Choong-Jae Lee, Hyeon-Ji Yun. Targeting the dysadherin/CA9 axis inhibits colorectal cancer adaptation and growth within the acidic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5111.