%0 Journal Article
%A Coleman, Olivia I
%A Sorbie, Adam
%A Riva, Alessandra
%A von Stern, Miriam
%A Kuhls, Stephanie
%A Selegato, Denise M
%A Siegert, Luisa
%A Keidel, Isabel
%A Köhler, Nikolai
%A Wirbel, Jakob
%A Kacprowski, Tim
%A Dunkel, Andreas
%A Pauling, Josch K
%A Plagge, Johannes
%A Mediel-Cuadra, Diego
%A Wagner, Sophia J
%A Chadly, Ines
%A Bierwith, Sandra
%A Peng, Tingying
%A Metzler, Thomas
%A Li, Xin-Feng
%A Heikenwälder, Mathias
%A Schafmayer, Clemens
%A Hinz, Sebastian
%A Röder, Christian
%A Röcken, Christoph
%A Zimmermann, Michael
%A Rosenstiel, Philip
%A Steiger, Katja
%A Jesinghaus, Moritz
%A Liebisch, Gerhard
%A Ecker, Josef
%A Schmidt, Christina
%A Zeller, Georg
%A Janssen, Klaus-Peter
%A Haller, Dirk
%T ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
%J Nature metabolism
%V nn
%@ 2522-5812
%C [London]
%I Springer Nature
%M DKFZ-2025-01825
%P nn
%D 2025
%Z epub
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40890536
%R 10.1038/s42255-025-01350-6
%U https://inrepo02.dkfz.de/record/304285