TY  - JOUR
AU  - Coleman, Olivia I
AU  - Sorbie, Adam
AU  - Riva, Alessandra
AU  - von Stern, Miriam
AU  - Kuhls, Stephanie
AU  - Selegato, Denise M
AU  - Siegert, Luisa
AU  - Keidel, Isabel
AU  - Köhler, Nikolai
AU  - Wirbel, Jakob
AU  - Kacprowski, Tim
AU  - Dunkel, Andreas
AU  - Pauling, Josch K
AU  - Plagge, Johannes
AU  - Mediel-Cuadra, Diego
AU  - Wagner, Sophia J
AU  - Chadly, Ines
AU  - Bierwith, Sandra
AU  - Peng, Tingying
AU  - Metzler, Thomas
AU  - Li, Xin-Feng
AU  - Heikenwälder, Mathias
AU  - Schafmayer, Clemens
AU  - Hinz, Sebastian
AU  - Röder, Christian
AU  - Röcken, Christoph
AU  - Zimmermann, Michael
AU  - Rosenstiel, Philip
AU  - Steiger, Katja
AU  - Jesinghaus, Moritz
AU  - Liebisch, Gerhard
AU  - Ecker, Josef
AU  - Schmidt, Christina
AU  - Zeller, Georg
AU  - Janssen, Klaus-Peter
AU  - Haller, Dirk
TI  - ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
JO  - Nature metabolism
VL  - nn
SN  - 2522-5812
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01825
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40890536
DO  - DOI:10.1038/s42255-025-01350-6
UR  - https://inrepo02.dkfz.de/record/304285
ER  -