MassIVE MSV000095581

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ATF6 promotes colorectal cancer growth and stemness by regulating the Wnt pathway

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Description

The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) homeostasis by sensing protein-folding stress and orchestrating cellular adaptation via the ER-transmembrane proteins IRE1, PERK and ATF6. Malignant cells can co-opt UPR signaling by IRE1 and PERK to sustain tumor growth; however, the importance of ATF6 in cancer remains poorly deciphered. We observed elevated ATF6 transcriptional activity in several cancers including colorectal carcinoma (CRC). Genetic silencing or small molecule inhibition of ATF6 blocked cell cycle progression and reduced viability of several human CRC cell lines in vitro and disrupted tumor progression in vivo. Unexpectedly, ATF6 interference also disabled Myc and Wnt signaling and reduced stemness. ATF6 inhibition attenuated growth of organoids derived from malignant but not normal human intestinal tissue, reducing Wnt-pathway activity and driving cellular differentiation. Wnt-surrogate agonism rescued the growth inhibitory phenotype of ATF6 interference. Our findings identify ATF6 as an unexpected facilitator of oncogenic Wnt signaling in CRC. [doi:10.25345/C54Q7R22M] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: ATF6, IRE1, unfolded protein response, Wnt signaling pathway

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Principal Investigators:
(in alphabetical order) 		Avi Ashkenazi, Genentech, Inc., USA
Submitting User: vpham
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