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

Coleman, O. I.; Sorbie, A.; Bierwirth, S.; Koevilein, J.; von Stern, M.; Koehler, N.; Wirbel, J.; Schmidt, C.; Kacprowski, T.; Dunkel, A.; Pauling, J. K.; Plagge, J.; Miedel-Cuadra, D.; Wagner, S.; Peng, T.; Metzler, T.; Schafmayer, C.; Hinz, S.; Roeder, C.; Roecken, C.; Stecher, B.; Rosenstiel, P.; Steiger, K.; Jesinghaus, M.; Liebisch, G.; Ecker, J.; Zeller, G.; Janssen, K.-P.; Haller, D.

doi:10.1101/2023.11.03.565267

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bioRxiv · 10.1101/2023.11.03.565267

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

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Abstract

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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565267v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@be3756org.highwire.dtl.DTLVardef@231da4org.highwire.dtl.DTLVardef@16f3aaeorg.highwire.dtl.DTLVardef@1758fe3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Chronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiota C_FIG O_LIBiallelic expression of activated ATF6 (p50 nuclear fragment) in intestinal epithelial cells (nATF6IEC) induces spontaneous colon tumors in SPF but not GF mice C_LIO_LIMechanistically, biallelic SPF nATF6IEC mice alter colonic lipid metabolism, including the upregulation of LCFAs and Fasn C_LIO_LIInhibition of FASN prevents colon tumor formation in mice, and reduces the tumor-promoting potential of the intestinal microbiota (FMT) C_LIO_LIExposure of fl/fl control mouse microbiota to LCFAs ex vivo translationally activates tumor-associated bacteria, including Desulfovibrio fairfieldensis C_LIO_LIHuman CRC patients show ATF6 upregulation, FASN co-occurrence and increased LCFAs in T tissue C_LIO_LIATF6 activity links with CRC-associated microbiota in patients, including Desulfovibrio C_LI Created with BioRender.com nATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.

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Coleman, O. I., Sorbie, A., Bierwirth, S., Koevilein, J., von Stern, M., Koehler, N., Wirbel, J., Schmidt, C., Kacprowski, T., Dunkel, A., Pauling, J. K., Plagge, J., Miedel-Cuadra, D., Wagner, S., Peng, T., Metzler, T., Schafmayer, C., Hinz, S., Roeder, C., Roecken, C., Stecher, B., Rosenstiel, P., Steiger, K., Jesinghaus, M., Liebisch, G., Ecker, J., Zeller, G., Janssen, K.-P., Haller, D.. 2023-11-05. ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation. https://doi.org/10.1101/2023.11.03.565267

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