ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway

Abstract The unfolded protein response maintains endoplasmic reticulum homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the endoplasmic reticulum transmembrane proteins IRE1, PERK, and ATF6. Malignant cells can co-opt IRE1 and PERK to sustain growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers, including colorectal carcinoma. Genetic silencing or small-molecule inhibition of ATF6 blocked cell-cycle progression and reduced viability of several human colorectal cancer cell lines in vitro, and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference disabled Wnt and Myc signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, decreasing Wnt pathway activity and driving cellular differentiation. Wnt-surrogate agonism in a Wnt ligand-dependent colorectal cancer organoid restored pathway activity and rescued growth under ATF6 blockade. Our findings uncover ATF6 as an unexpected facilitator of oncogenic Wnt signaling in colorectal cancer. Significance: ATF6 intervention reduces colorectal cancer cell and organoid viability by interrupting dysregulated Wnt signaling, identifying a novel facilitator and potential therapeutic target in colorectal cancer.