The dysadherin/carbonic anhydrase 9 axis shapes an acidic tumor microenvironment to promote colorectal cancer progression

TL;DR

This study shows how a protein called dysadherin helps colorectal cancer grow by making the tumor environment more acidic, and suggests it could be a target for treatment.

Contribution

The study identifies a new mechanism by which dysadherin promotes cancer progression through the integrin/FAK/STAT3/CA9 pathway and tumor acidification.

Findings

Dysadherin expression correlates with increased tumor acidity and poor CRC progression.

Dysadherin activates the integrin/FAK/STAT3 pathway to upregulate carbonic anhydrase 9 (CA9).

Deleting dysadherin reduces metastasis in acidic tumor environments, but restoring CA9 rescues this effect.

Abstract

The tumor microenvironment (TME) plays a central role in cancer progression and metastasis. A key feature of the TME is extracellular acidity, which promotes disease progression, immune evasion, and drug resistance. Tumor acidity is increasingly recognized as a critical factor in cancer development and a negative prognostic indicator. Here, we demonstrate that the membrane glycoprotein dysadherin promotes colorectal cancer (CRC) malignancy by modulating TME acidity. Comprehensive bioinformatics and pathological analyses of CRC patient samples revealed that increased tumor acidity is a hallmark of CRC progression and strongly correlates with high expression of dysadherin. Functional studies confirmed that dysadherin enhances malignant traits, particularly under acidic conditions. Mechanistically, dysadherin activates the integrin/FAK/STAT3 signaling pathway, leading to the upregulation of carbonic anhydrase 9 (CA9). CA9 facilitates proton export, contributing to extracellular acidification while maintaining intracellular pH homeostasis, thereby enabling cancer cells to survive and thrive in acidic environments. In a murine liver metastasis model, dysadherin deletion impaired cellular adaptation to the acidic TME and markedly attenuated metastatic colonization, whereas restoring CA9 expression effectively rescued metastatic potential. Overall, our findings identify the dysadherin/CA9 axis as a potential therapeutic target in CRC and provide new insights into how tumors exploit acidosis to drive malignant development and progression.

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