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      The Fungal Mycobiome Promotes Pancreatic Oncogenesis via MBL Activation

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          Abstract

          Bacterial dysbiosis has emerged as an accomplice to carcinogenesis in malignancies such as colon and liver cancer, and we have recently implicated the microbiome in the pathogenesis of pancreatic ductal adenocarcinoma (PDA) 1 . However, the mycobiome has not been clearly implicated in tumorigenesis. We found that fungi migrate from the gut lumen to the pancreas. PDA tumors harbored a ~3000-fold increase in fungi compared to normal pancreas in both mice and humans. The composition of the PDA mycobiome was distinct from that of gut or normal pancreas based on alpha and beta diversity indices. Specifically, the fungal community infiltrating PDA tumors was markedly enriched for Malassezia in both mice and humans. Fungal ablation was tumor-protective in slowly progressive and invasive models of PDA whereas repopulation with Malassezia – but not Candida, Saccharomyces, or Aspergillus – accelerated oncogenesis. In parallel, we discovered that ligation of mannose-binding lectin (MBL), which binds fungal wall glycans to activate the complement cascade, was required for oncogenic progression whereas MBL or C3 deletion in the extra-tumoral compartment or C3aR knockdown in tumor cells were protective. Further, reprogramming of the mycobiome did not alter PDA progression in Mbl or C3 deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade via MBL activation.

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          Most cited references9

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          Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse.

          To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
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            Advancing our understanding of the human microbiome using QIIME.

            High-throughput DNA sequencing technologies, coupled with advanced bioinformatics tools, have enabled rapid advances in microbial ecology and our understanding of the human microbiome. QIIME (Quantitative Insights Into Microbial Ecology) is an open-source bioinformatics software package designed for microbial community analysis based on DNA sequence data, which provides a single analysis framework for analysis of raw sequence data through publication-quality statistical analyses and interactive visualizations. In this chapter, we demonstrate the use of the QIIME pipeline to analyze microbial communities obtained from several sites on the bodies of transgenic and wild-type mice, as assessed using 16S rRNA gene sequences generated on the Illumina MiSeq platform. We present our recommended pipeline for performing microbial community analysis and provide guidelines for making critical choices in the process. We present examples of some of the types of analyses that are enabled by QIIME and discuss how other tools, such as phyloseq and R, can be applied to expand upon these analyses. © 2013 Elsevier Inc. All rights reserved.
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              Depletion of Murine Intestinal Microbiota: Effects on Gut Mucosa and Epithelial Gene Expression

              Background Inappropriate cross talk between mammals and their gut microbiota may trigger intestinal inflammation and drive extra-intestinal immune-mediated diseases. Epithelial cells constitute the interface between gut microbiota and host tissue, and may regulate host responses to commensal enteric bacteria. Gnotobiotic animals represent a powerful approach to study bacterial-host interaction but are not readily accessible to the wide scientific community. We aimed at refining a protocol that in a robust manner would deplete the cultivable intestinal microbiota of conventionally raised mice and that would prove to have significant biologic validity. Methodology/Principal Findings Previously published protocols for depleting mice of their intestinal microbiota by administering broad-spectrum antibiotics in drinking water were difficult to reproduce. We show that twice daily delivery of antibiotics by gavage depleted mice of their cultivable fecal microbiota and reduced the fecal bacterial DNA load by 400 fold while ensuring the animals' health. Mice subjected to the protocol for 17 days displayed enlarged ceca, reduced Peyer's patches and small spleens. Antibiotic treatment significantly reduced the expression of antimicrobial factors to a level similar to that of germ-free mice and altered the expression of 517 genes in total in the colonic epithelium. Genes involved in cell cycle were significantly altered concomitant with reduced epithelial proliferative activity in situ assessed by Ki-67 expression, suggesting that commensal microbiota drives cellular proliferation in colonic epithelium. Conclusion We present a robust protocol for depleting conventionally raised mice of their cultivatable intestinal microbiota with antibiotics by gavage and show that the biological effect of this depletion phenocopies physiological characteristics of germ-free mice.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                6 September 2019
                02 October 2019
                October 2019
                02 April 2020
                : 574
                : 7777
                : 264-267
                Affiliations
                [1 ]S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY 10016
                [2 ]Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, 345 E. 24th Street, New York, NY 10010
                [3 ]Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016
                [4 ]Biology Department, Brooklyn College NY 11210 and Biology/Biochemistry Programs, Graduate Center (CUNY), New York, NY 10016
                [5 ]Department of Cell Biology New York University School of Medicine, 550 First Avenue, New York, NY 10016
                Author notes
                [*]

                Contributed equally

                [#]

                Co-senior authors

                Author Contributions

                B.A. ( berk.aykut@ 123456nyulangone.org ) carried out in vivo and in vitro experiments, study design, PCR, analysis and interpretation, manuscript preparation, and statistical analysis; S.P. ( sp117@ 123456nyu.edu ) carried out fungal DNA sequencing, analysis and interpretation, manuscript preparation, and statistical analysis; R.C. ( rc3266@ 123456nyu.edu ) carried out in vivo experiments, histological analysis, and manuscript preparation; Q.L. ( ql770@ 123456nyu.edu ) performed computational analyses and provided critical review; R.A. ( raquelabengozar@ 123456yahoo.es ) carried out in vivo experiments and provided technical assistance; J.I.K. ( jacqueline.kim@ 123456nyulangone.org ) carried out in vivo experiments and provided critical review; S.A.S. ( sorinarmanalberto.shadaloey@ 123456nyulangone.org ) carried out mouse breeding and histology; D.W. ( emmawudongling@ 123456gmail.com ) performed tissue culture and cell line generation; P.P. ( pamela_preiss@ 123456gmx.de ) provided technical assistance and carried out in vivo experiments; N.V. ( narendra.verma@ 123456nyulangone.org ) carried out knockdown experiments; Y.G. ( yg701@ 123456nyu.edu ) carried out PCR; A.S. ( asaxena@ 123456brooklyn.cuny.edu ) performed FISH and provided critical review; M.V. ( mridula.vardhan@ 123456gmail.com ) carried out DNA extraction and contributed to computational analysis; B.D. ( brian.diskin@ 123456nyulangone.org ) carried out in vivo experiments and critical review; W.W. ( wei.wang3@ 123456nyulangone.org ) provided technical assistance; J.L. ( joshua.leinwand@ 123456nyulangone.org ) provided critical review and contributed to study design; E.K. ( emma.kurz@ 123456nyulangone.org ) carried out in vivo experiments and contributed to study design; J.A.K.R. ( juan.kochenrossi@ 123456nyulangone.org ) provided technical assistance and contributed to study design; M.H. ( mautinhundeyin@ 123456gmail.com ) carried out in vivo experiments; C.Z. ( zambri@ 123456gmail.com ) carried out human sample collection; X.L. ( xl15@ 123456nyu.edu ) provided technical assistance; D.S. ( ds100@ 123456nyu.edu ) and G.M. ( george.miller@ 123456nyulangone.org ) conceived, designed, supervised, analyzed, and interpreted the study, prepared the manuscript, and provided critical review.

                Address correspondence to: George Miller, MD, Departments of Surgery and Cell Biology, New York University School of Medicine, 435 East 30th Street, Room 417, New York, NY 10016, Tel: (646) 501-2208, Fax: (212) 263-6840, george.miller@ 123456nyumc.org , Deepak Saxena, Ph.D, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, 345 E. 24th Street, Room 921B, New York, NY 10010, Tel.: (212) 998-9256, ds100@ 123456nyu.edu
                Correspondence and requests for materials should be addressed to G.M. or D.S.
                Article
                NIHMS1539230
                10.1038/s41586-019-1608-2
                6858566
                31578522
                6e69a858-b10b-4561-a7a2-a27f29c1de3e

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                Uncategorized
                pancreatic cancer,fungi,mbl,complement
                Uncategorized
                pancreatic cancer, fungi, mbl, complement

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