Endoplasmic reticulum unfolded protein responses (UPRER) contribute to cancer development and the activating transcription factor 6 (ATF6) is involved in microbiota-dependent tumorigenesis. Here, we substantiate the clinical relevance of ATF6 in early-onset and late colorectal cancer patient cohorts. Transcriptional analysis in intestinal epithelial cells (IEC) of ATF6 transgenic mice (nATF6IEC) identified bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype-labeling confirmed ATF6-related enrichment of long chain fatty acids in colonic tissue of patients, mice and organoid cultures. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirmed the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumor-relevant microbial taxa was mechanistically linked to long chain fatty acid exposure, using bioorthogonal non-canonical amino acid tagging (BONCAT) and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signaling in the epithelium to select for tumor-promoting microbiota by altering lipid metabolism.Competing Interest StatementThe authors have declared no competing interest.
Authors
Olivia I. Coleman, Adam Sorbie, Alessandra Riva, Miriam von Stern, Stephanie Kuhls, Denise M. Selegato, Nikolai Köhler, Jakob Wirbel, Tim Kacprowski, Andreas Dunkel, Josh K. Pauling, Johannes Plagge, Diego Mediel-Cuadra, Sophia Wagner, Ines Chadly, Sandra Bierwith, Tingying Peng, Thomas Metzler, Clemens Schafmayer, Sebastian Hinz, Christian Röder, Christoph Röcken, Michael Zimmermann, Philip Rosenstiel, Katja Steiger, Moritz Jesinghaus, Gerhard Liebisch, Josef Ecker, Christina Schmidt, Georg Zeller, Klaus-Peter Janssen, Dirk Haller