Diet Induced Hyperlipidemia Confers Resistance to Standard Therapy in Pancreatic Cancer by Selecting for "Tumor Protective" Microbial Metabolites and Treatment Refractory Cells

Obesity causes a number of systemic alterations including chronic inflammation and changes in gut microbiome. However, whether these actively contribute to poor survival and therapy resistance in patients with pancreatic cancer remain undetermined. Our current study shows that high fat diet fed pancreatic tumor bearing mice do not respond to standard of care therapy with gemcitabine and paclitaxel when compared to corresponding control diet fed mice. Upon fecal matter transplant from control mice to high fat diet fed mice, the tumors became sensitive to standard of care therapy and showed extensive cell death. Analysis of gut microbiome showed an enrichment of queuosine (Q) producing bacteria in high fat diet fed mice and an enrichment of S-adenosyl methionine (SAM) producing bacteria in control diet fed mice. Further, treatment of high fat diet fed animals with SAM recapitulated the observation with lean to obese fecal matter transplant. Additionally, treatment of pancreatic and colon cancer cell lines in vitro with Q promoted resistance to the paclitaxel and oxaliplatin respectively, while treatment with SAM promoted sensitivity to these drugs. Treatment of pancreatic cancer cells with Q showed upregulation PRDX1, that is involved in oxidative stress protection. Analysis of tumor tissues in high fat diet fed mice showed high PRDX1, low apoptosis and increased proliferation, which were reversed upon treatment with SAM as well as by lean to obese fecal matter transplant. In parallel, high fat diet fed mice showed increase in CD133+ treatment refractory population compared to the control animals. Interestingly, treatment with Q in vitro did not enrich for CD133+ population, indicating that Q mediated protection from cell death was independent of enrichment of treatment refractory cells. These observations indicated that microbial metabolite Q accumulated in high fat diet fed mice protected tumors from chemotherapy induced oxidative stress by upregulating PRDX1. This protection could be reversed by treatment with SAM. We conclude that relative concentration of S-adenosyl methionine and queuosine in fecal samples of pancreatic cancer patients can be indicative of therapy response in this disease. ### Competing Interest Statement University of Minnesota has a patent for Minnelide, which has been licensed to Minneamrita Therapeutics, LLC. SB is a consultant with Minneamrita Therapeutics LLC and this relationship is managed by University of Miami. The remaining authors declare no conflict of interest.