# Regulation of Pancreatic Oncogenesis by the Gut Microbiome

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $375,150

## Abstract

Summary
Pancreatic ductal adenocarcinoma (PDA) is the 5th leading cancer diagnosis in the USA and is highly lethal.
There are no effective means to prevent or delay PDA onset and few effective treatment options exist once
transformation has occurred. Bacterial dysbiosis is emerging as an accomplice to carcinogenesis in extra-
pancreatic malignancies such as colon and liver cancer. Nevertheless, the gut microbiome has not been clearly
implicated in carcinomas remote from the intestinal lumen or its drainage. There are tangential data, however,
that support an association between PDA and gut bacteria. For example, the oral microbiome in patients with
PDA has been found to substantially differ from control subjects. Further, our laboratories have obtained critical
preliminary data which suggest that the intestinal microbiome may be an important regulator of PDA
development in genetically predisposed hosts: (i) We found that intraluminal gut bacteria can directly access the
pancreas; (ii) The relative abundance of select bacterial taxa was higher in the gut of PDA patients compared
with healthy individuals; (iii) Specific pattern recognition receptors (PRRs), which transduce inflammation in
response to microbial pathogens, are highly expressed in the PDA tumor microenvironment (TME) and
activation of these receptors accelerates tumorigenesis whereas mice deficient in select PRRs have slower
progression of PDA; (iv) Endo-luminal administration of pathogenic bacteria accelerates tumorigenesis in
genetically predisposed mice whereas germ-free mice are protected from PDA. (v) Select bacterial byproducts
induce recruitment of regulatory T cells, M2-polarized macrophages, and myeloid derived suppressor cells to
the PDA TME. Based on these data, we postulate that pathogenic gut bacteria drive pancreatic
oncogenesis in at-risk hosts via activation of specific PRRs which leads to pathogen-induced immune
suppression. In Aim 1 we will define the gut and intra-pancreatic microbiome in mice developing PDA
compared with WT mice, we will contrast the microbial phenotypes associated with aggressive PDA compared
with slowly progressive cancer in genotypically identical hosts, and determine whether humans with PDA harbor
a distinct gut and pancreatic microbiome compared with age-matched control patients. In Aim 2, we will test our
hypothesis that gut microbes influence oncogenesis by examining whether directly modulating the microbiome
alters the rate of tumor progression. As such, we will identify the specific endoluminal bacteria which affect the
progression of pancreatic oncogenesis. In Aim 3, we will test our hypothesis that select luminal pathogens
promote pancreatic tumorigenesis by inducing immune suppression via ligation of select Toll-like receptors and
NOD-like receptors. Our experiments will provide critical new information on the mechanism of
pancreatic oncogenesis. We will also identify novel risk factors and provide guidance for the
development of innova...

## Key facts

- **NIH application ID:** 10070580
- **Project number:** 5R01CA206105-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DIANE M SIMEONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,150
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070580

## Citation

> US National Institutes of Health, RePORTER application 10070580, Regulation of Pancreatic Oncogenesis by the Gut Microbiome (5R01CA206105-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10070580. Licensed CC0.

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