TY  - JOUR
AU  - Tintelnot, Joseph
AU  - Xu, Yang
AU  - Lesker, Till R
AU  - Schönlein, Martin
AU  - Konczalla, Leonie
AU  - Giannou, Anastasios D
AU  - Pelczar, Penelope
AU  - Kylies, Dominik
AU  - Puelles, Victor G
AU  - Bielecka, Agata A
AU  - Peschka, Manuela
AU  - Cortesi, Filippo
AU  - Riecken, Kristoffer
AU  - Jung, Maximilian
AU  - Amend, Lena
AU  - Bröring, Tobias S
AU  - Trajkovic-Arsic, Marija
AU  - Siveke, Jens
AU  - Renné, Thomas
AU  - Zhang, Danmei
AU  - Boeck, Stefan
AU  - Strowig, Till
AU  - Uzunoglu, Faik G
AU  - Güngör, Cenap
AU  - Stein, Alexander
AU  - Izbicki, Jakob R
AU  - Bokemeyer, Carsten
AU  - Sinn, Marianne
AU  - Kimmelman, Alec C
AU  - Huber, Samuel
AU  - Gagliani, Nicola
TI  - Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer.
JO  - Nature 
VL  - 615
IS  - 7950
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2023-00390
SP  - 168-174
PY  - 2023
N1  - 2023 Mar;615(7950):168-174
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36813961
DO  - DOI:10.1038/s41586-023-05728-y
UR  - https://inrepo02.dkfz.de/record/271258
ER  -