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

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.