The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL

• Published in: Nature (London) 2019-10, Vol.574 (7777), p.264-267
• Main Authors: Aykut, Berk, Pushalkar, Smruti, Chen, Ruonan, Li, Qianhao, Abengozar, Raquel, Kim, Jacqueline I., Shadaloey, Sorin A., Wu, Dongling, Preiss, Pamela, Verma, Narendra, Guo, Yuqi, Saxena, Anjana, Vardhan, Mridula, Diskin, Brian, Wang, Wei, Leinwand, Joshua, Kurz, Emma, Kochen Rossi, Juan A., Hundeyin, Mautin, Zambrinis, Constantinos, Li, Xin, Saxena, Deepak, Miller, George
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/51; 14; 14/1; 14/32; 38; 38/22; 45; 45/77; 45/90; 59; 631/67/327; 64; 64/110; 692/308/575; Ablation; Adenocarcinoma; Adenocarcinoma - immunology; Adenocarcinoma - microbiology; Adenocarcinoma - pathology; Analysis; Animal models; Animals; Carcinogenesis; Carcinogens; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - microbiology; Carcinoma, Pancreatic Ductal - pathology; Case-Control Studies; Clonal deletion; Colon; Colon cancer; Complement Activation; Complement C3 - deficiency; Complement C3 - immunology; Complement component C3; Complement component C3a; Complement receptors; Control; Disease Progression; Diversity indices; Dysbacteriosis; Female; Fungi; Gastrointestinal Microbiome - immunology; Gene expression; Growth; Humanities and Social Sciences; Humans; Invasiveness; Lectins; Letter; Liver cancer; Malassezia; Male; Mannan-binding lectin; Mannose; Mannose-binding lectin; Mannose-Binding Lectin - immunology; Mice; Mice, Inbred C57BL; Microbiota (Symbiotic organisms); multidisciplinary; Mycobiome - immunology; Pancreas; Pancreatic cancer; Pancreatic tumors; Pathogenesis; Peer review; Physiological aspects; Polysaccharides; Repopulation; Science; Science (multidisciplinary); Tumorigenesis; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1608-2

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA) 1 . However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species—but not species in the genera Candida , Saccharomyces or Aspergillus —accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment—or knockdown of C3aR in tumour cells—were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl - (also known as Mbl2 ) or C3 -deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL. In humans and mouse models, the mycobiome of pancreatic ductal adenocarcinoma tumours is markedly enriched in Malassezia species compared to that of normal pancreas, which implicates these pathogenic fungi in oncogenesis.