Differential Progression of Pancreatic Premalignancy in Geographically Distinct Murine Cohorts Uncovers Key Role of Microbial Metabolite

Rian M. Howell (Advisor: Florencia McAllister, MD)

          The composition of the gut microbiome has been demonstrated to have wide reaching effects on human physiology. As of late, microbiota has gained attention for the role it plays in influencing pancreatic cancer, both in terms of responses to therapeutic modalities and implications on survivorship. The functional mechanisms by which bacterial communities affect initiation and progression of pancreatic cancer and premalignant lesions, however, remains to be fully elucidated. We serendipitously observed contrasting phenotypes in transgenic mouse models of pancreatic premalignancy raised in geographically distant facilities, regardless of a common lineage. Upon further exploration, distinct gut microbial compositions were detected in both cohorts and fecal microbial transfer between animals significantly accelerated tumorigenesis at the facility with slow phenotype.  We then interrogated downstream effects of respective bacterial colonization by examining the unique metabolic profiles and gene expression signatures in the pancreata from both cohorts. We found that succinic acid was increased not only in the serum of transgenic mice, but also within the pre-cancerous lesions in the pancreas from the mice displaying the exacerbated phenotype. Addition of a known succinic acid producing bacteria, as well as the resulting bacterial supernatant to murine derived pancreatic explant cells demonstrated increased pro-tumorigenic activity as characterized by increased rates of transformation and expression of HIF1α and various HIF1α target genes in established pancreatic cancer cell lines. This succinic acid mediated effect on HIF1α expression was also observed in an independent cohort of mice belonging to a separate PDAC model further validating these findings. Taken together, these data demonstrate the ability of gut microbes to affect systemic metabolic pathways that can ultimately affect pancreatic cancer initiation and progression. Furthermore, we propose a causal link between bacteria present in the gut and a metabolite that has been identified as clinically relevant.

Advisory Committee:

• Florencia McAllister, MD, Chair
• Shin-Heng Chiou, PhD
• Michael Kim, MD
• Gregory Lizee, PhD
• Guillermina Lozano, PhD
• Paul Scheet, PhD