Dataset Information

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation

ABSTRACT:

The induction of endoplasmic reticulum unfolded protein responses (UPRER) contributes to cancer development and progression. We recently linked microbiota-related triggers to the tumor-promoting role of signal transducer activating transcription factor 6 (ATF6) in the colon. Here we substantiate the clinical relevance of ATF6 and related bacterial genera in colorectal cancer patient cohorts. Spatial and longitudinal bacterial profiling in ATF6 transgenic mice (nATF6IEC) identified tumor-initiating and tumor-progressing shifts in the mucosa-associated microbiota. Transcriptional analysis in intestinal epithelial cells (IEC) of germ-free and specific pathogen-free nATF6IEC mice defined bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics, isotope-labeling in intestinal organoids and FASN inhibition confirmed ATF6-mediated involvement of long-chain fatty acids in tumorigenesis. Multi-omics data integration identified a bacteria-lipid network characterized by fatty acid efflux, catabolism and detoxification. We postulate chronic ATF6 signaling to drive a clinically relevant pathologic response altering lipid metabolism to select for a tumor-promoting microbiota.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase

PROVIDER: MTBLS7387 | MetaboLights | 2025-07-02

REPOSITORIES: MetaboLights

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			Action	DRS
	ND001_10188n_NormalTissue_C18neg_20240212.cef	Other
	ND001_10188t_TumorTissue_C18neg_20240212.cef	Other
	ND001_101n_NormalTissue_C18neg_20240212.cef	Other
	ND001_101t_TumorTissue_C18neg_20240212.cef	Other
	ND001_103n_NormalTissue_C18neg_20240212.cef	Other

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

Coleman Olivia I OI Sorbie Adam A Riva Alessandra A von Stern Miriam M Kuhls Stephanie S Selegato Denise M DM Siegert Luisa L Keidel Isabel I Köhler Nikolai N Wirbel Jakob J Kacprowski Tim T Dunkel Andreas A Pauling Josch K JK Plagge Johannes J Mediel-Cuadra Diego D Wagner Sophia J SJ Chadly Ines I Bierwith Sandra S Peng Tingying T Metzler Thomas T Li Xin X Heikenwälder Mathias M Schafmayer Clemens C Hinz Sebastian S Röder Christian C Röcken Christoph C Zimmermann Michael M Rosenstiel Philip P Steiger Katja K Jesinghaus Moritz M Liebisch Gerhard G Ecker Josef J Schmidt Christina C Zeller Georg G Janssen Klaus-Peter KP Haller Dirk D

Nature metabolism 20250901 9

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 chang ...[more]

PMID: 40890536

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