Pancreatic Fungal Communities Are Linked to Pancreatic Cancer

Recently, it has been shown that the pancreatic microbiome is a contributor to pathogenesis in pancreatic ductal adenocarcinoma (PDAC). Building on this unexpected finding, Aykut, Pushalkar, and colleagues discovered a role for the mycobiome (the fungal version of the microbiome) in PDAC. Experiments in mice indicated that fungi could migrate to the pancreas within 30 minutes of oral administration, demonstrating that it is possible for gut fungi to colonize the pancreas. Although the mycobiomes of wild-type mice and mice genetically predisposed to pancreatic cancer were similar at first, they differed at 30 weeks, and PDAC tumors exhibited an increase in intratumoral fungi. Similar results were seen in patients; notably, the mycobiomes of pancreata from patients with PDAC differed substantially from those of healthy pancreata. Further, several experiments provided preliminary evidence for a causal relationship between components of the pancreatic mycobiome and PDAC pathogenesis. Mycobiome ablation or treatment with the antifungal agent amphotericin B in two mouse PDAC models protected against PDAC progression and potentiated gemcitabine-based chemotherapy. Following amphotericin B treatment, repopulation with one fungal species found more commonly in PDAC tumors than in normal tissue (Malassezia globosa) accelerated the growth of PDAC tumors, whereas this was not the case with other commensal fungal species. Deletion of the gene encoding the mannose-binding lectin MBL, a protein that activates the lectin pathway of the complement cascade upon recognition of pathogenic fungi, protected against PDAC tumor development in the mice, as did deletion of the gene encoding complement component 3 (C3). These results indicate a previously unknown, MBL–C3 dependent role for the pancreatic mycobiome in PDAC, providing a basis for further work that may uncover disease biomarkers or aid in the development of new therapies.

Aykut B, Pushalkar S, Chen R, Li Q, Abengozar R, Kim JI, et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 2019;574:264–7.

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