ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation
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<sup>IEC</sup>) 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<sup>IEC</sup> 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.
Authors
- Sophia J. Wagner (ORCID: https://orcid.org/0000-0003-3763-2282)
- Katja Steiger (ORCID: https://orcid.org/0000-0002-7269-5433)
- Thomas J. Metzler (ORCID: https://orcid.org/0000-0002-1620-5559)
- Mathias Heikenwälder (ORCID: https://orcid.org/0000-0002-3135-2274)
- Moritz Jesinghaus (ORCID: https://orcid.org/0000-0002-0018-5661)
- Christoph Röcken (ORCID: https://orcid.org/0000-0002-6989-8002)
- Michael Zimmermann (ORCID: https://orcid.org/0000-0002-5797-3589)
- Dirk Haller (ORCID: https://orcid.org/0000-0002-6977-4085)
- Georg Zeller (ORCID: https://orcid.org/0000-0003-1429-7485)
- Nikolai Köhler (ORCID: https://orcid.org/0000-0002-5103-883X)
- Olivia I. Coleman (ORCID: https://orcid.org/0000-0002-4075-7820)
- Josef Ecker (ORCID: https://orcid.org/0000-0003-4799-0788)
- Gerhard Liebisch (ORCID: https://orcid.org/0000-0003-4886-0811)
- Andreas Dunkel (ORCID: https://orcid.org/0000-0002-4445-6144)
- Clemens Schafmayer (ORCID: https://orcid.org/0000-0002-4096-5005)
- Jakob Wirbel (ORCID: https://orcid.org/0000-0002-4073-3562)
- Philip Rosenstiel (ORCID: https://orcid.org/0000-0002-9692-8828)
- Christina Schmidt (ORCID: https://orcid.org/0000-0002-3867-0881)
- Stephanie Kuhls
- Tingying Peng (ORCID: https://orcid.org/0000-0002-7881-1749)
- Klaus‐Peter Janssen (ORCID: https://orcid.org/0000-0002-4707-7887)
- Tim Kacprowski (ORCID: https://orcid.org/0000-0002-5393-2413)
- Johannes Plagge (ORCID: https://orcid.org/0000-0002-7180-8221)
- Christian Röder (ORCID: https://orcid.org/0000-0001-7881-9110)
- Alessandra Riva (ORCID: https://orcid.org/0000-0002-5724-7616)
- Adam Sorbie (ORCID: https://orcid.org/0000-0002-3330-4612)
- Diego Mediel-Cuadra
- Sandra Bierwith
- Xin Li (ORCID: https://orcid.org/0000-0003-0896-8713)
- Miriam von Stern
- Sebastian Hinz (ORCID: https://orcid.org/0000-0001-9350-9196)
- Josch K. Pauling
- Luisa Siegert
- Denise M. Selegato
- Ines Chadly
- Isabel Keidel (ORCID: https://orcid.org/0009-0000-9806-1087)
Institutions
- Munich University of Applied Sciences (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Universitätsklinikum Gießen und Marburg (DE)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- Weihenstephan-Triesdorf University of Applied Sciences (DE)
- University Hospital Regensburg (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Medizinische Hochschule Hannover (DE)
- Research Institute for Work, Technology and Culture (DE)
- Helmholtz Centre for Infection Research (DE)
- Bernstein Center for Computational Neuroscience Tübingen (DE)
- European Molecular Biology Laboratory (DE)
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich (DE)
- European Molecular Biology Laboratory (DE)
- University Hospital Carl Gustav Carus (DE)
- University of Rostock (DE)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s42255-025-01350-6
- Citations
- 4
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22