The Pancreatic Microbiome is Associated with Carcinogenesis and Worse Prognosis in Males and Smokers

Abstract

An intra-pancreatic microbiota was recently discovered in several prominent studies. Since pancreatic adenocarcinoma (PAAD) is one of the most lethal cancers worldwide, and the intratumor microbiome was found to be a significant contributor to carcinogenesis in other cancers, this study aims to characterize the PAAD microbiome and elucidate how it may be associated with PAAD prognosis. We further explored the association between the intra-pancreatic microbiome and smoking and gender, which are both risk factors for PAAD. RNA-sequencing data from The Cancer Genome Atlas (TCGA) were used to infer microbial abundance, which was correlated to clinical variables and to cancer and immune-associated gene expression, to determine how microbes may contribute to cancer progression. We discovered that the presence of several bacteria species within PAAD tumors is linked to metastasis and immune suppression. This is the first large-scale study to report microbiome-immune correlations in human pancreatic cancer samples. Furthermore, we found that the increased prevalence and poorer prognosis of PAAD in males and smokers are linked to the presence of potentially cancer-promoting or immune-inhibiting microbes. Further study into the roles of these microbes in PAAD is imperative for understanding how a pro-tumor microenvironment may be treated to limit cancer progression.

Tumor-Associated Microbiome: Where Do We Stand?

“…Chakladar et al profiled the intra-tumor pancreatic microbiome through large-scale sequencing data from The Cancer Genome Atlas (TCGA) (187 pancreatic cancer samples). The authors found that the increased prevalence and poorer prognosis of PDAC in males and smokers were linked to the presence of potentially cancer-promoting or immune-inhibiting microbes (most of them belonged to Proteobacteria phylum) [ 86 ]. Another study showed that intra-tumor Gammaproteobacteria in PDAC modulates tumor sensitivity to gemcitabine, one of the few active and standard of care chemotherapy drugs used in PDAC [ 38 ].…”

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

“…Of note, elevated levels of Proteobacteria were detected in fecal samples of patients with PDAC [41,45], making stool analysis an attractive, cheap, and non-invasive method to detect intrapancreatic microbial shifts. Some studies showed elevated levels of intratumoral Enterobacteriaceae, which also correlated with poor prognosis [35,37]. Moreover, another intestinal bacterium, Enterococcus faecalis, was identified within juice and tissue samples of PDAC-patients [40].…”

“…The analysis of pancreatic samples and fluids from patients with PDAC compared to samples from patients with a healthy organ or with benign pathologies provided evidence that the pancreas is not a sterile organ [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ] ( Table 1 ). In particular, the analysis of pancreatic cystic fluid revealed a specific bacterial ecosystem which may reflect the microbiota harbored within the pancreas [ 39 ].…”

“…The most prominent microbes identified in pancreatic tissue samples and associated with PDAC are Gram-negative bacteria, more specifically from the phylum Proteobacteria [ 35 , 44 ]. Pushalkar et al directly compared pancreatic and fecal samples, showing especially for Proteobacteria an increased presence in the pancreas tissue.…”

“…Among Proteobacteria genera, Pseudomonas were the most abundant in PDAC [ 41 ]. Thomas et al also detected increased Proteobacteria in human PDAC tissue [ 42 ] while Chakladar et al showed an association for some members of the classes Betaproteobacteria and Gammaproteobacteria with poor patient prognosis [ 35 ]. Analogously, Geller et al showed an elevated presence of Gammaproteobacteria in tissue samples of subjects with PDAC [ 37 ], however, results of another study showed enrichment of the genus Pseudoxathomonas of the classes Gammaproteobacteria within the pancreas among PDAC long-term survivors [ 43 ].…”