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研究揭示真菌促进胰腺癌发生的机制
2019-10-03 20:53

美国纽约大学医学院George Miller和Deepak Saxena等研究人员合作发现,真菌群落通过激活甘露糖结合凝集素(MBL)促进胰腺癌发生。2019年10月2日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现真菌从肠腔迁移到胰腺,这与胰腺导管腺癌(PDA)的发病机制有关。与正常的胰腺组织相比,这种癌症的人和小鼠模型中的PDA肿瘤显示出约3000倍的真菌增加。基于α-和β-多样性指数,PDA肿瘤的真菌群落的组成与肠道或正常胰腺的组成不同。具体而言,浸润型PDA肿瘤的真菌群落明显富集了马拉色菌属,这在小鼠和人类中都一样。在PDA的缓慢进展和侵袭性模型中,真菌群落的消除可防止肿瘤生长,而马拉色菌属物种(念珠菌、酿酒酵母或曲霉属中的物种则不然)的繁殖可加速肿瘤发生。

研究人员还发现,甘露糖结合凝集素(MBL)的连接是肿瘤进展所必需的,其与真菌壁的聚糖结合以激活补体级联,而瘤外区MBL或C3的缺失或C3aR的敲低肿瘤细胞都可以防止肿瘤生长。此外,在Mbl-(也称为Mbl2)或C3缺陷型小鼠中,对真菌群落的重编程不会改变PDA的进程。

总的来说,这项研究表明,致病真菌通过激活MBL来驱动补体级联反应,从而促进PDA的生长。

据悉,细菌稳态失调伴随着结肠癌和肝癌等恶性肿瘤的癌变,并且最近发现其与PDA的发病机理有关。但是,尚未有研究明确将真菌群落与肿瘤发生关联起来。

附:英文原文

Title: The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL

Author: Berk Aykut, Smruti Pushalkar, Ruonan Chen, Qianhao Li, Raquel Abengozar, Jacqueline I. Kim, Sorin A. Shadaloey

Issue&Volume: 2019-10-02

Abstract: 

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.

DOI: 10.1038/s41586-019-1608-2

Source: https://www.nature.com/articles/s41586-019-1608-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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