The Microbiome in PDAC-Vantage Point for Future Therapies?

Abstract

Microorganisms have been increasingly implicated in the pathogenesis of malignant diseases, potentially affecting different hallmarks of cancer. Despite the fact that we have recently gained tremendous insight into the existence and interaction of the microbiome with neoplastic cells, we are only beginning to understand and exploit this knowledge for the treatment of human malignancies. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor with limited therapeutic options and a poor long-term survival. Recent data have revealed fascinating insights into the role of the tumoral microbiome in PDAC, with profound implications for survival and potentially therapeutic outcomes. In this review, we outline the current scientific knowledge about the clinical and translational role of the microbiome in PDAC. We describe the microbial compositions in healthy and tumoral pancreatic tissue and point out four major aspects of the microbiome in PDAC: pathogenesis, diagnosis, treatment, and prognosis. However, caution must be drawn to inherent pitfalls in analyzing the intratumoral microbiome. Among others, contamination with environmental microbes is one of the major challenges. To this end, we discuss different decontamination approaches that are crucial for clinicians and scientists alike to foster applicability and physiological relevance in this translational field. Without a definition of an exact and reproducible intratumoral microbial composition, the exploitation of the microbiome as a diagnostic or therapeutic tool remains theoretical.

Keywords: biomarker; contamination; microbiome; pancreatic ductal adenocarcinoma.

Figure 1

Sources of contamination and recommended controls in tumoral microbiome analysis. Microbial contamination during sample preparation is impossible to avoid. Considering the low biomass of tumor microbiomes, contaminants from the environment, paraffin (in case of FFPE samples), reagents from DNA extraction kits, PCR, and library preparation can outnumber the real tumor-derived microbial count. Thus, a thorough decontamination protocol should be mandatory. Ideally, negative controls are implemented at each processing step for every single sample batch. However, real tumoral taxa can also occur in negative controls due to computational cross-contamination. Here, an index switch in multiplexed analysis is introduced by sequencing errors (barcode leakage). Desoxyribonucleic acid (DNA), polymerase chain reaction (PCR), formalin-fixed paraffin-embedded (FFPE).

Figure 2

Potential involvement of the microbiome in (pancreatic) oncogenesis. There is growing evidence on how different microbiomes contribute to carcinogenesis, e.g., via promoting oncogenic signaling, direct and indirect genetic alterations, chronic inflammation, and interaction with the immune system and secretion of microbe-derived metabolites. However, most of these theories have yet to be validated in PDAC patients. Tumor microenvironment (TME); mutant p53 (mutp53); pancreatic ductal adenocarcinoma (PDAC); oral squamous cell carcinoma (OSCC); desoxyribonucleic acid (DNA); double-strand break (DSB); microbe-associated molecular pattern (MAMP); lipopolysaccharide (LPS); pattern recognition receptor (PRR); myeloid-derived suppressor cell (MDSC); short-chain fatty acid (SCFA); epithelial-to-mesenchymal transition (EMT); and pondus hydrogenii (pH).