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@ARTICLE{Tintelnot:271258,
      author       = {J. Tintelnot and Y. Xu and T. R. Lesker and M. Schönlein
                      and L. Konczalla and A. D. Giannou and P. Pelczar and D.
                      Kylies and V. G. Puelles and A. A. Bielecka and M. Peschka
                      and F. Cortesi and K. Riecken and M. Jung and L. Amend and
                      T. S. Bröring and M. Trajkovic-Arsic$^*$ and J. Siveke$^*$
                      and T. Renné and D. Zhang and S. Boeck and T. Strowig and
                      F. G. Uzunoglu and C. Güngör and A. Stein and J. R.
                      Izbicki and C. Bokemeyer and M. Sinn and A. C. Kimmelman and
                      S. Huber and N. Gagliani},
      title        = {{M}icrobiota-derived 3-{IAA} influences chemotherapy
                      efficacy in pancreatic cancer.},
      journal      = {Nature},
      volume       = {615},
      number       = {7950},
      issn         = {0028-0836},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2023-00390},
      pages        = {168-174},
      year         = {2023},
      note         = {2023 Mar;615(7950):168-174},
      abstract     = {Pancreatic ductal adenocarcinoma (PDAC) is expected to be
                      the second most deadly cancer by 2040, owing to the high
                      incidence of metastatic disease and limited responses to
                      treatment1,2. Less than half of all patients respond to the
                      primary treatment for PDAC, chemotherapy3,4, and genetic
                      alterations alone cannot explain this5. Diet is an
                      environmental factor that can influence the response to
                      therapies, but its role in PDAC is unclear. Here, using
                      shotgun metagenomic sequencing and metabolomic screening, we
                      show that the microbiota-derived tryptophan metabolite
                      indole-3-acetic acid (3-IAA) is enriched in patients who
                      respond to treatment. Faecal microbiota transplantation,
                      short-term dietary manipulation of tryptophan and oral 3-IAA
                      administration increase the efficacy of chemotherapy in
                      humanized gnotobiotic mouse models of PDAC. Using a
                      combination of loss- and gain-of-function experiments, we
                      show that the efficacy of 3-IAA and chemotherapy is licensed
                      by neutrophil-derived myeloperoxidase. Myeloperoxidase
                      oxidizes 3-IAA, which in combination with chemotherapy
                      induces a downregulation of the reactive oxygen species
                      (ROS)-degrading enzymes glutathione peroxidase 3 and
                      glutathione peroxidase 7. All of this results in the
                      accumulation of ROS and the downregulation of autophagy in
                      cancer cells, which compromises their metabolic fitness and,
                      ultimately, their proliferation. In humans, we observed a
                      significant correlation between the levels of 3-IAA and the
                      efficacy of therapy in two independent PDAC cohorts. In
                      summary, we identify a microbiota-derived metabolite that
                      has clinical implications in the treatment of PDAC, and
                      provide a motivation for considering nutritional
                      interventions during the treatment of patients with cancer.},
      cin          = {ED01},
      ddc          = {500},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36813961},
      doi          = {10.1038/s41586-023-05728-y},
      url          = {https://inrepo02.dkfz.de/record/271258},
}