Abstract
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 present 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. A combination of 16s pyrosequencing and whole-genome sequencing of gut microbiota in a spontaneous genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC) 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 found to be 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 promote inflammation and release metabolites that foster host tumorigenesis, thereby fulfilling the ‘vicious cycle hypothesis’ of the role of the microbiome in health and disease states. Our results provide a potential, precise, non-invasive tool for early detection of PDAC, which will result in improved outcomes.
Author Summary Pancreatic cancer is among the deadliest cancers that affects almost 54,000 patients in United States alone, with 90% of them succumbing to the disease. Lack of early detection is considered to be the foremost reason for such dismal survival rates. Our study shows that resident gut microbiota is altered at the early stages of tumorigenesis much before development of observable tumors in a spontaneous, genetically engineered mouse model for pancreatic cancer. Upon reconstruction of active metabolic pathways within the altered microbial flora using bioinformatics tools, we observed a distinct upregulation of polyamine and nucleotide biosynthetic pathways. The metabolic products of this pathway (namely polyamines) are typically utilized by rapidly dividing cells for proliferation that occurs during tumorigenesis. Our results showed that in our mouse models of pancreatic cancer (that recapitulates the clinical stages of tumor development), there was elevated serum polyamine concentration at early stages of tumorigenesis. This was further validated in pancreatic cancer patient serum samples. These observations are highly significant as they indicate that a precise and noninvasive tool can be developed as an early detection marker for pancreatic cancer which is likely to have a positive effect on not only survival but overall prognosis for this disease.