Abstract 2002: A blood-based microbial metabolites signature for associated with metastatic duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

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Abstract Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic and metabolomic-based analysis of resected dpNET tissues from MEN1 patients revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to Faecalibacterium prausnitzii, Faecalibacterium nucleatum, and Klebsiella pneumoniae and negatively correlated with Streptococcus pneumoniae and Streptococcus thermophilus. A microbial-associated uremic toxin panel (MUTP) was developed and the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95% CI: 0.85-1.00) with 67% sensitivity at 95% specificity for identifying MEN1 patients with metastatic dpNETS in an independent validation cohort. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in a Men1fl/flPdx1-CreTg mouse model of MEN1 pancreatic neuroendocrine tumors. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may identify individuals who are at risk of having metastatic dpNETs to better guide clinical management and intervention. Citation Format: Riccardo Ballarò, Amanda R. Wasylishen, Carolina R. Pieterman, Courtney Olsen, Ehsan Irajizad, Ranran Wu, Hiroyuki Katayama, Huiling Liu, Yining Cai, Jennifer Dennison, Steven Waguespack, Kim-Ahn Do, Sunita Agarwal, Mary Walter, James Welch, Lee Weinstein, Jenny E. Blau, Smita Jha, Naris Nilubol, Menno R. Vriens, Rachel S. van Leeuwaarde, Mark J. van Treijen, Gerlof D. Valk, Nancy D. Perrier, Samir M. Hanash, Johannes F. Fahrmann. A blood-based microbial metabolites signature for associated with metastatic duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2002.

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