Microbial Dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer

Abstract

Synopsis:Gut microbiota changes during early stages of pancreatic ductal adenocarcinoma (PDAC) progression and contributes towards host polyamine pool. Both changes can be used as an early predictive marker for PDAC. Short title: Whole genome sequencing of PDAC microbiomeWord count: 4,735 Translational RelevancePancreatic carcinogenesis progresses through pre-cancerous PanIN lesions to invasive cancer. Even though these morphological changes are histologically distinct, imaging techniques are not able to distinguish the pre-invasive PanINs from normal pancreas, making detection of a tumor at a precancerous stage impossible . Thus, majority of cases (85-90%) present with advanced pancreatic cancer at the time of diagnosis. This contributes to the dismal survival rate in this disease. Our study of gut microbiome analysis on KPC mice during tumor progression followed by metabolic reconstruction and experimental validation in human samples indicate that gut-microbiome analysis along with an analysis of the microbial metabolites can be developed as potential biomarkers for detection of PDAC at early stages when histological changes are not yet grossly apparent. AbstractPurpose: The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated to the abysmal survival rate in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high-risk for PDAC. Experimental Design:A combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota was used in a spontaneous genetically engineered PDAC murine model (KRAS G12D TP53 R172H Pdx Cre or KPC). Metabolic reconstruction of microbiome was done using the HUmanN2 pipeline. Serum polyamine levels were measured from murine and patient samples using standard methods. Results:Results showed a progressive Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated.These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentration. Therefore, at the early stages of tumorigenesis, the gut microbial composition changes in a way to release metabolites that foster host tumorigenesis, thereby fulfilling the 'vicious cycle hypothesis' of the role of the microbiome in health and disease states. Conclusions:Our results provide a potential, precise, non-invasive tool for early detection of PDAC, which will result in improved outcomes.

Microbiota-Derived Metabolites in Tumor Progression and Metastasis

“…Moreover, polyamines such as cadaverine and putrescine showed a higher abundance in the CRC group with respect to the healthy cohort, suggesting a role as potential biomarkers [ 50 ]. Along with these aspects, studies on pancreatic ductal adenocarcinoma (PDAC) in mouse models have showed that the early dysbiosis occurrence is responsible for the high concentration of polyamines in PDAC mice and patients, suggesting the possibility to measure these metabolites for early detection purposes [ 51 ].…”

Current State of “Omics” Biomarkers in Pancreatic Cancer

“…In an animal study, Mendez et al [151] demonstrated a substantial correlation between microbial dysbiosis and the release of tumor-inducing metabolites in the earlystage, while showing significantly elevated serum polyamine concentrations in PDAC patients; this may be postulated as a predictive biomarker for early detection of pancreatic cancer. It is among the current assumptions that bacteria in the pancreatic microbiome may contribute to the resistance of gemcitabine, which is widely used in the treatment of PDAC.…”

Onkobiózis és mikrobiális metabolikus jelátvitel pancreas-adenocarcinomában

“…A mikrobiom és a PA közötti kapcsolat ötlete először akkor merült fel, amikor felfedezték, hogy a Helicobacter pylorikolonizáció pancreatitishez társul (27). Azóta több hasonló összefüggést mutattak ki a szájüreg (28), a bélrendszer (29), a pancreas (18,30,31) és a széklet (20,32) mikrobiomja, a mycobiom (33) és a PA között. Jelenlegi ismereteink szerint a szájüregi-, gyomor-és bélmikrobiom alkotórészei gyulladást kelthetnek.…”