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<p>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 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 nATF6<sup>IEC</sup> mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including <i>Desulfovibrio fairfieldensis</i>, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of <i>Desulfovibrio</i> isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月1日

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  • Olivia I. Coleman,
  • Adam Sorbie,
  • Alessandra Riva,
  • Miriam von Stern,
  • Stephanie Kuhls,
  • Denise M. Selegato,
  • Luisa Siegert,
  • Isabel Keidel,
  • Nikolai Köhler,
  • Jakob Wirbel,
  • Tim Kacprowski,
  • Andreas Dunkel,
  • Josch K. Pauling,
  • Johannes Plagge,
  • Diego Mediel-Cuadra,
  • Sophia J. Wagner,
  • Ines Chadly,
  • Sandra Bierwith,
  • Tingying Peng,
  • Thomas Metzler,
  • Xin Li,
  • Mathias Heikenwälder,
  • 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

摘要

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.