The fungal microbiome promotes pancreatic cancer via activation of mannose-binding lectin !!!!

These GEITP pages have discussed many papers about “our microbiome” the bacteria (and fungi and viruses) that actually comprise ~92% of all the DNA in “our body” (yes, our DNA only makes up 8% of the total ☹). As well as intestinal gut microbiota, our microbiome includes every orifice and skin area where these bugs are able to thrive. Communities of microorganisms that occupy specific regions of the body are often altered in a patient with cancer, and these microbiomes — particularly their bacterial components — are a current focus of cancer research. This topic lies within the GEITP theme of gene-environment interactions.

Today’s example is pancreatic ductal adenocarcinoma (PDA), in which changes in bacterial community occupying the pancreas have been documented. This lethal disease often goes undetected until it has reached advanced stages, in which case the prognosis is usually very poor. Authors [see attached article & editorial] show that the fungal component of the pancreatic microbiome (known as the mycobiome) is also altered in PDA. In fact, an abundance of a specific fungal genus — actually promotes the disease…!!

The mycobiome is a historically underrecognized player in human health and disease, but its role in both is essential. Harmless organisms called commensals (individuals of two species in which one species obtains food or other benefits from the other — without either harming or benefiting the latter), including fungi, inhabit mucosal surfaces such as the linings of the gut, nose and mouth, and

can activate inflammatory processes as part of the immune system’s response to injury or infection. In some cases, changes in biodiversity of fungal communities can be linked to aggravated inflammatory-disease outcomes. For example, intestinal overgrowth of Candida albicans — a fungus that causes oral thrush in babies — has been associated with severe forms of intestinal ulcers and with mold-induced asthma. Furthermore, it is becoming apparent that there is a relationship between the gut mycobiome and human cancers — including colorectal and esophageal cancer.

Authors [see attached article] demonstrated that fungi migrate from the intestinal lumen — up the bile duct in retrograde flow — into the pancreas, and that this migration of fungus is implicated in the pathogenesis of PDA. PDA tumors in humans and mouse models of this cancer exhibit a (~3,000-fold) increase in fungi, compared to normal pancreatic tissue…!! The composition of the mycobiome of PDA tumours was distinct from that of the gut or of normal pancreas — on the basis of “alpha- and beta-diversity indices” (specifically, the fungal community that infiltrates PDA tumors is markedly enriched for Malassezia spp. in both mouse and human). Ablation of the mycobiome was protective against tumor growth in slowly progressive and invasive (mouse) models of PDA, and repopulation with a Malassezia species — but not species in the genera Candida, Saccharomyces or Aspergillus — accelerated oncogenesis (i.e. development of a tumor).

Authors also discovered that ligation (joining together of two molecules) of mannose-binding lectin (MBL) — which binds to glycans in the fungal wall to activate the complement cascade — was required for tumor progression. On the contrary, deletion of MBL or complement-3 (C3) in the (outside-the-tumor) compartment — or knockdown of the C3aR gene in tumor cells — were both protective against cancer growth. In addition, authors found that reprogramming of the mycobiome did not alter progression of PDA in Mbl- or C3-deficient mice. Together, this really cool study shows that pathogenic fungi promote PDA, by driving the complement cascade, via activation of MBL. 😊


Nature 10 Oct 2019; 574: 264-267 & News/N/Views editorial pp 184-185

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