Journal Article

DKFZ-2025-01825

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.

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. J. ; Chadly, I. ; Bierwith, S. ; Peng, T. ; Metzler, T. ; Li, X.-F.DKFZ* ; Heikenwälder, M.DKFZ* ; Schafmayer, C. ; Hinz, S. ; Röder, C. ; Röcken, C. ; Zimmermann, M. ; Rosenstiel, P. ; Steiger, K. ; Jesinghaus, M. ; Liebisch, G. ; Ecker, J. ; Schmidt, C. ; Zeller, G. ; Janssen, K.-P. ; Haller, D.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s42255-025-01350-6

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.

Note: epub

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Contributing Institute(s):

1. Chronische Entzündung und Krebs (D440)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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