Coleman, Olivia I. and Sorbie, Adam and Riva, Alessandra and von Stern, Miriam and Kuhls, Stephanie and Selegato, Denise M. and Siegert, Luisa and Keidel, Isabel and Kohler, Nikolai and Wirbel, Jakob and Kacprowski, Tim and Dunkel, Andreas and Pauling, Josch K. and Plagge, Johannes and Mediel-Cuadra, Diego and Wagner, Sophia J. and Chadly, Ines and Bierwith, Sandra and Peng, Tingying and Metzler, Thomas and Li, Xin and Heikenwalder, Mathias and Schafmayer, Clemens and Hinz, Sebastian and Roder, Christian and Rocken, Christoph and Zimmermann, Michael and Rosenstiel, Philip and Steiger, Katja and Jesinghaus, Moritz and Liebisch, Gerhard and Ecker, Josef and Schmidt, Christina and Zeller, Georg and Janssen, Klaus-Peter and Haller, Dirk (2025) ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation. NATURE METABOLISM, 7 (9). ISSN , 2522-5812
Full text not available from this repository. (Request a copy)Abstract
Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYDROGEN-SULFIDE; GENE-EXPRESSION; GUT MICROBIOTA; DNA-DAMAGE; R PACKAGE; ACID; CANCER; SYNTHASE; MS; VISUALIZATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2026 10:30 |
| Last Modified: | 26 Mar 2026 10:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67999 |
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