Type 2 diabetes induced microbiome dysbiosis is associated with therapy resistance in pancreatic adenocarcinoma

Kousik Kesh,Sulagna Banerjee,Roberto Mendez,Santanu Banerjee,Leila Abdelrahman

doi:10.1186/s12934-020-01330-3

Abstract

Resistance to therapy is one of the major factors that contribute to dismal survival statistics in pancreatic cancer. While there are many tumor intrinsic and tumor microenvironment driven factors that contribute to therapy resistance, whether pre-existing metabolic diseases like type 2 diabetes (T2D) contribute to this has remained understudied. It is well accepted that hyperglycemia associated with type 2 diabetes changes the gut microbiome. Further, hyperglycemia also enriches for a “stem-like” population within the tumor. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to gemcitabine/paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group. Additionally, we also observed an increase in the CD133+ tumor cells population in the T2D model. These observations indicated that in an animal model for T2D, microbial dysbiosis is associated with increased resistance to chemotherapeutic compounds.

Highlights

Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55,000 patients being diagnosed in 2019 alone and nearly as many succumbing to it
Our results further showed that, tumors implanted in the type 2 diabetes (T2D) mice responded poorly to standard of care chemotherapy in pancreatic cancer, gemcitabine/paclitaxel (Gem/Pac) compared to those in the control group
After continuous administration of streptozotocin for 5 days, the T2D group was fed a high-fat diet (42% Cal from fat, TD.88137, ENVIGO) for 4 weeks to establish a model of type 2 diabetes

Summary

Introduction

Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55,000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. This disease has been projected to emerge as the 2nd most common of cancer related deaths in United. While there have been extensive studies at the tumor intrinsic as well as around the contributions of the microenvironment towards the aggressive biology of pancreatic tumors, not a lot of research has been focused on the contributions of systemic factors in its poor outcome. Studies have shown that pancreatic cancer patients with T2D have poor survival statistics [6].

Methods

Results

Conclusion