MiR-210 Signaling Is an Important Regulator of Microbiome-Mediated Modulation of Pancreatic Cancer Progression

INTRODUCTION: Therapeutic options are limited in advanced stage pancreatic cancer. Depletion of microbiome has been shown to decrease tumor burden in pancreatic cancer preclinical models. microRNAs regulate cancer cell response to surrounding tumor microenvironmental cues. miR-210 is one such microRNA induced during hypoxia that regulates metabolic adaptations of tumor cells. Modulating microbiome to treat pancreatic carcinogenesis is an attractive therapeutic option. We sought to investigate this by studying the impact of genetic deletion of miR-210 in context of microbiome depletion. METHODS: Syngeneic pancreatic cancer cell lines (WT KPC) were developed with miR-210 deletion via CRISPR-Cas9 method (miR-210 KO cells). Then miR-210 KO cells were injected orthotopically into pancreas of mir-210 KO mice. For control, WT KPC cells were injected into WT (C57/B6) mice. Tumor growth and immune infiltration were measured at endpoint by flowcytometry. Microbiome depletion was achieved in both these groups by oral gavage and systemic delivery of antibiotics. RESULTS: There was decrease in tumor growth in WT mice that had microbiome depletion as previously reported. Interestingly, in the group with miR-210 KO cells, there was no effect on tumor growth seen on microbiome depletion, suggesting miR-210 signaling is important in modulating microbiome induced tumor progression. Flow cytometry analyses showed increase in number of myeloid-derived suppressor cells in microbiome depleted miR-210 KO tumors. CONCLUSION: These results show that microbiome-induced carcinogenesis is regulated by miR-210 signaling. Augmenting miR-210 signaling and its downstream effectors may reveal therapeutic targets that can be used to devise novel treatment for pancreatic cancer.