Gut-Tumor Axis Mediated by a Microbiome-Derived tRNA Modification
Abstract
Breast cancer is not one disease but instead refers to a variety of types that each derive from distinct causes and therefore merit different treatments. In fact, a single breast tumor may be comprised of in situ cancer, limited to the local area in the breast, and invasive cancer that has spread to other breast tissues or areas of the body (see http://www.cancer.org). For treatments, it is critical to apply a variety of options that target a wide range of cellular mechanisms. It is crucial to develop new classes of molecules that target heretofore unexplored cellular mechanisms, so that tumors not responsive to a particular treatment might be responsive to these new routes of therapy. This proposal will explore a new and previously under-appreciated avenue that links the breast cancer prevention and development with the gut microbes in the mammals. A fundamental step from DNA to protein is translation where the amino acid sequence information encoded by the gene is decoded by transfer RNAs (tRNAs). Each human cell type has well-defined levels and patterns of various tRNAs to allow regulation of protein synthesis. tRNAs are also heavily modified chemically; a specific form of modification is the queuosine (Q) that is derived from a micronutrient generated by our gut microbes. This proposal combines the distinct but complementary expertise of the Principal Investigator (PI) and Co-Investigator (Co-I). PI Sun is an expert in mammalian gut biology, microbiome, and cancer. Findings from the Sun lab led to the understanding of the host-bacterial interactions in inflammation and cancer. Co-I Pan is an expert in tRNA biology; his lab was the first to demonstrate tRNA overexpression in breast cancer and study its functional consequences. His lab also developed the method to measure tRNA Q-modification levels and has applied it to investigate the evolution of coding sequences. In the current Department of Defense (DoD) award, we found that Q-modification regulates genes critical in cell proliferation, tight junctions, and migration in human breast cancer cells in vitro and a breast tumor mouse model in vivo. We found evidence that microbiome was involved in the growth of breast cancer in vivo. To extend the results from the current DoD project, we will take a two-pronged approach to identify cellular pathways and gut microbiome effects that are altered in breast tumors in a tRNA Q-modification dependent manner. The first approach utilizes our recent developed tRNA sequencing technology to characterize secreted tRNA fragments in cells and in breast tumors in situ as well as functions of gut microbiome in mouse models. The second approach uses genetic and chemical disruption of the tRNA Q-modification pathway in mouse models of breast cancer, where we can alter the microbiome compositions as well as microbiome-host interactions through tRNA Q-modification. Our study could reveal a new paradigm on linking gut microbiome to breast cancer through this dynamic RNA modification. The innovation of our study includes: (i) Conceptual framework: Our finding of micronutrient and abnormal microbiome and breast cancer risk is novel. Our proposed concept that microbiome-derived tRNA Q-modification levels affect cellular processes may have broader implication in understanding the pathophysiology of breast cancer. (ii) Therapeutic potential for breast cancer: Our findings in restoration of microbiome and intestinal function will open a new avenue for prebiotics/probiotics in the prevention and inhibit growth of breast cancer. (iii) State-of-the-art experimental models and technology: We have established novel molecular biology methods and animal model to study dysbiosis and Q-modification in breast cancer. These tools can also be used to evaluate the potential beneficial effects of micronutrient and microbiome for prevention and treatment of breast cancer. Impact: Gut microbes have become increasingly important in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010623
Entities
People
- Jun Sun
Organizations
- United States Army
- University of Illinois at Chicago