Prospective Study of Human Oral Microbiome and Pancreatic Cancer Risk
In this U01 application, we focus on the oral mycobiome (fungal microbiome). We hypothesize that oral fungi, potentially in conjunction with the bacterial microbiota11, potentiate pancreas carcinogenesis via the pancreas tumor immune microenvironment. Inflammation/immunity is critical to pancreas carcinogenesis. Our preliminary data show that oral fungal and bacterial types are present in pancreas tumor tissue10. We also found that Dectin 1, a major high-specificity fungal receptor12, is highly expressed in human pancreas tumors, and that Dectin 1 ligation by fungus experimentally promotes pancreas cancer and peri-tumoral immune response (Nature Medicine, 201713). Oral fungal dysbiosis is linked to immune and inflammatory responses14, digestive diseases15, 16, and cancer40, 41. Taken together, these data strongly support our hypothesis. The current research gaps, however, are a lack of prospective evaluation of the link between oral fungi and pancreatic cancer risk, and a limited understanding of their functional roles in human pancreas tumor inflammation/immunity and carcinogenesis.
We propose a multi-disciplinary study to examine the relationship of the oral and pancreatic mycobiome, and their functions, to pancreatic cancer risk. Pancreatic cancer is highly lethal (93% of patients die within 5 years of diagnosis) and little is known about ways to prevent this dreadful disease. Our ultimate goal is to identify specific oral microbiota in the general population which may be managed to prevent pancreatic cancer and to detect it early.
Aim 1. To test the hypothesis that oral fungi influence subsequent risk of pancreatic cancer development.
a. Using ITS gene sequencing fungal microbiome assay from pre-diagnostic oral wash samples, we will test if oral fungi are associated with subsequent risk of pancreatic cancer in a nested case-control study (360 cases and 360 controls), within the NCI-Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II (ACS-CPS II) cohorts. We expect to identify specific oral fungi associated with subsequent risk of pancreatic cancer.
Sub-aim: Using existing 16S gene sequencing data on oral bacteria in these cohorts8, we will test if the relationships of oral fungi and pancreas cancer risk differ according to oral bacterial status.
b. Using ITS gene sequencing and confirmatory Sanger sequencing in oral wash samples and pancreatic tumor tissue, we will test if pancreatic cancer risk-associated oral fungi (Aim 1-a) are found in the pancreas microbiome from 100 treatment naive pancreatic cancer patients at NYU. We expect to find that risk-associated oral fungi are present in pancreas cancer tissue and to confirm that fungi of the same clonal origin are found both in the pancreas and the oral cavity of these subjects.
Aim 2. To test the hypothesis that metabolically active fungi in the pancreas influence tumor immunity.
Using high-content flow cytometry and tissue immunohistochemistry in pancreatic tumor tissue from 100 pancreas cancer patients (as in Aim 1b), we will examine if pancreas tumor fungal microbiome is associated with the density, location, and activation state of tumor infiltrating myeloid and lymphoid cells. As control, we will examine these relationships in adjacent normal tissue (100 cancer patients) and, as a secondary control, in tumor-free pancreatic samples (cadavers=40). We expect to find that risk-associated fungi influence innate and adaptive immunity in tumors and modify the tumor immune environment.
Jiyoung Ahn (New York University School of Medicine)
Richard B. Hayes (New York University School of Medicine)