ORCID Profile
0000-0001-8514-1395
Current Organisation
University Medical Center Hamburg-Eppendorf
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Publisher: Springer Science and Business Media LLC
Date: 22-02-2023
DOI: 10.1038/S41586-023-05728-Y
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 treatment 1,2 . Less than half of all patients respond to the primary treatment for PDAC, chemotherapy 3,4 , and genetic alterations alone cannot explain this 5 . 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.
Publisher: American Society for Clinical Investigation
Date: 10-01-2023
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 14-08-2020
DOI: 10.1126/SCIIMMUNOL.ABA4163
Abstract: CD4 + T RM 17 cells become activated by inflammatory cytokines to produce IL-17A and thereby promote autoimmunity.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-02-2021
DOI: 10.1126/SCIIMMUNOL.ABF6692
Abstract: Tissue-resident memory-like T H 17 cells are clonally expanded in bronchoalveolar lavage fluid of patients with severe COVID-19.
Publisher: Springer Science and Business Media LLC
Date: 10-2018
DOI: 10.1038/S12276-018-0157-3
Abstract: Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially O-glycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O-glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant O-glycans might be relevant for pathogenic mechanisms of the pancreas.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Wiley
Date: 12-2021
Abstract: The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical s les with ex les of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer‐reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state‐of‐the‐art handbook for basic and clinical researchers.
No related grants have been discovered for Nicola Gagliani.