TY - JOUR
T1 - The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL
AU - Aykut, Berk
AU - Pushalkar, Smruti
AU - Chen, Ruonan
AU - Li, Qianhao
AU - Abengozar, Raquel
AU - Kim, Jacqueline I.
AU - Shadaloey, Sorin A.
AU - Wu, Dongling
AU - Preiss, Pamela
AU - Verma, Narendra
AU - Guo, Yuqi
AU - Saxena, Anjana
AU - Vardhan, Mridula
AU - Diskin, Brian
AU - Wang, Wei
AU - Leinwand, Joshua
AU - Kurz, Emma
AU - Kochen Rossi, Juan A.
AU - Hundeyin, Mautin
AU - Zambrinis, Constantinos
AU - Li, Xin
AU - Saxena, Deepak
AU - Miller, George
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/10/10
Y1 - 2019/10/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-1608-2
DO - 10.1038/s41586-019-1608-2
M3 - Article
C2 - 31578522
AN - SCOPUS:85074201113
SN - 0028-0836
VL - 574
SP - 264
EP - 267
JO - Nature
JF - Nature
IS - 7777
ER -