Abstract
Pancreatic cancer is a lethal cancer with aggressive and invasive characteristics. By the time it is diagnosed, patients already have tumors extended to other organs and show extremely low survival rates. The gut microbiome is known to be associated with many diseases and its imbalance affects the pathogenesis of pancreatic cancer. In this study, we established an orthotopic, patient-derived xenograft model to identify how the gut microbiome is linked to pancreatic ductal adenocarcinoma (PDAC). Using the 16S rDNA metagenomic sequencing, we revealed that the levels of Alistipes onderdonkii and Roseburia hominis decreased in the gut microbiome of the PDAC model. To explore the crosstalk between the two bacteria and PDAC cells, we collected the supernatant of the bacteria or cancer cell culture medium and treated it in a cross manner. While the cancer cell medium did not affect bacterial growth, we observed that the A. onderdonkii medium suppressed the growth of the pancreatic primary cancer cells. Using the bromodeoxyuridine/7-amino-actinomycin D (BrdU/7-AAD) staining assay, we confirmed that the A. onderdonkii medium inhibited the proliferation of the pancreatic primary cancer cells. Furthermore, RNA-seq analysis revealed that the A. onderdonkii medium induced unique transcriptomic alterations in the PDAC cells, compared to the normal pancreatic cells. Altogether, our data suggest that the reduction in the A. onderdonkii in the gut microbiome provides a proliferation advantage to the pancreatic cancer cells.
Graphical abstract
Key points
• Metagenome analysis of pancreatic cancer model reveals A. onderdonkii downregulation.
• A. onderdonkii culture supernatant suppressed the proliferation of pancreatic cancer cells.
• RNA seq data reveals typical gene expression changes induced by A. onderdonkii.
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Data availability
For metagenome data, SRA records will be accessible with the following link https://www.ncbi.nlm.nih.gov/sra/PRJNA733811.
For other raw data, Supplementary material is available online.
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This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant number: 2021R1A2C2005472) and a grant from the Asan Institute for Life Sciences (Grant No. 2020IP0036-1).
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KL and HJO designed the study. KL and M-SK collected the data, performed the main experiments, and wrote the manuscript. SK, SA, and MJK helped with the experiments. SC and S-WK supervised the research progress, led this study, and edited the manuscript. All authors reviewed and approved the manuscript.
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For the generation of PDX model of pancreatic cancer, procedure for animal experiment was inspected and approved by the Institutional Animal Care and Use Committees (IACUC) of the Asan Institute for Life Sciences (AILS, Project Number: 2019–14-367).
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Lee, K., Oh, H.J., Kang, MS. et al. Metagenomic analysis of gut microbiome reveals a dynamic change in Alistipes onderdonkii in the preclinical model of pancreatic cancer, suppressing its proliferation. Appl Microbiol Biotechnol 105, 8343–8358 (2021). https://doi.org/10.1007/s00253-021-11617-z
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DOI: https://doi.org/10.1007/s00253-021-11617-z