Reduced chloride channel accessory 4 (CLCA4) levels are linked to cancer development, while its role and mechanism in cancer stem cells (CSCs) remain unclear. In this study, we discovered that decreased CLCA4 expression was evident in CD133⁺CD44⁺ colorectal CSCs and chemoresistant colorectal cancer (CRC) cells. Increased expression of CLCA4 inhibited the expression of stemness genes, reduced tumorsphere formation, suppressed the self-renewal, migratory, and invasive capabilities of colorectal CSCs in vitro, and suppressed the tumorigenicity of colorectal CSCs in vivo. Mechanistically, CLCA4 interacted with vimentin, leading to FAK pathway inactivation and subsequent suppression of CSC expansion, while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal. Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens. Increased CLCA4 expression promoted the infiltration of cytotoxic CD8⁺ T cells and enhanced the anti-PD-1 therapeutic efficacy. Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway, potentially reducing tumor cell stemness and evading immune surveillance. The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by insidious onset and lack of effective therapy. The molecular pathogenesis of PDA remains to be understood fully. Transcriptional factor GATA6 is an important transcriptional regulator in normal pancreas development, particularly in the initial specification and differentiation of the pancreas. Recent studies have linked pancreatic malignancy closely to GATA6. Increased levels of GATA6 expression enhance pancreatic cancer cell growth. GATA6 emerges as a lineage-specific oncogenic factor in PDA, augmenting the oncogenic phenotypes of PDA cells upon its overexpression. However, elevated GATA6 levels are correlated with well-differentiated tumors and a more favorable patient prognosis. Experimental evidence in genetic mouse models has revealed a tumor-suppressive role for GATA6. The circumstantial roles of GATA6 in pancreatic tumorigenesis remain to be defined. This review aims to elucidate recent advances in comprehending GATA6, emphasizing its crucial roles in both pancreas physiology and pathology. Special attention will be given to its involvement in PDA pathogenesis, exploring its potential as a novel biomarker and a promising therapeutic target for PDA.