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Coleman, O.I.* ; Sorbie, A.* ; Riva, A.* ; von Stern, M.* ; Kuhls, S.* ; Selegato, D.M.* ; Siegert, L.* ; Keidel, I.* ; Köhler, N.* ; Wirbel, J.* ; Kacprowski, T.* ; Dunkel, A.* ; Pauling, J.K.* ; Plagge, J.* ; Mediel-Cuadra, D. ; Wagner, S. ; Chadly, I.* ; Bierwith, S.* ; Peng, T. ; Metzler, T.* ; Li, X.* ; Heikenwälder, M.* ; Schafmayer, C.* ; Hinz, S.* ; Roder, C.* ; Röcken, C.* ; Zimmermann, M.* ; Rosenstiel, P.* ; Steiger, K.* ; Jesinghaus, M.* ; Liebisch, G.* ; Ecker, J.* ; Schmidt, C.* ; Zeller, G.* ; Janssen, K.P.* ; Haller, D.*

ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.

Nat. Metab. 7, 1830–1850 (2025)

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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 (nATF6^IEC) 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 nATF6^IEC 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.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Hydrogen-sulfide; Hepatocellular-carcinoma; Gene-expression; Gut Microbiota; Dna-damage; R Package; Acid; Cancer; Synthase; Ms

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Volume: 7, Pages: 1830–1850

Publisher Springer

Publishing Place London

Reviewing status Peer reviewed

Institute(s) Helmholtz Artifical Intelligence Cooperation Unit (HAICU)

Grants Bundesministerium fur Bildung und Forschung (BMBF)
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Collaborative Research Center CRC1471
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Collaborative Research Center CRC 1371
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Collaborative Research Center CRC1335