Role of Bitter Taste Receptor TAS2R38 in Colorectal Cancer
Abstract
This application addresses the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Areas Topic Area of Colorectal Cancer (CRC). We will focus on establishing the role of TAS2R38 in CRC for future therapeutic interventions, to close the gap in the treatment of military members, Veterans, their beneficiaries, and the general public. The Principal Investigator (PI) is well trained in cancer biology and pharmacology and has experience in CRC. He has published several research articles in high impact factor journals. Research interests include understanding key signaling pathways in CRC and whether targeting them will contribute to improve treatment for cancer patients. This grant will help the PI generate data necessary to submit research project grant applications such as the Department of Defense (DoD) Idea and Breakthrough Awards and publish his work in a high impact factor journal. The PI’s career goal is to become an independent academic investigator focusing on CRC research to discover novel targets for prevention and therapy. The American Cancer Society estimated that 53,200 Americans would die due to CRC in 2020. Although the disease affects older people, recent statistics show an increase in younger populations. The disease is also a major problem in the Veteran population and every year about 4,000 Veterans and active military personnel are diagnosed with CRC. Key risk factors for CRC include high rates of smoking, dietary habits, high alcohol intake, and contact with hazardous infectious agents, all of which are commonly seen with the military personnel. A critical fact that is often underplayed is that the active-duty military personnel are especially vulnerable because they are exposed to cancer-associated risk factors in the line of duty during foreign country deployments, including various pathogens, and consequently develop inflammatory bowel disease (IBD). Studies have suggested that between 2 and 10 times higher numbers of military personnel (both active and retirees) are affected with IBD as compared to civilians. Furthermore, IBD is a significant risk factor for developing cancer. Hence, there is a dire need to identify novel signaling pathways that involve the immune system as targets for future CRC therapy. We have an organization within the cancer center where individuals with a lived experience of cancer as a survivor, caregiver, or someone who is at high risk for cancer get together on a periodic basis to discuss various bedside observations with investigators. During one of these meetings, the PI heard from a caregiver of an interesting observation related to a patient experiencing bitter taste before being diagnosed with cancer. This led to his drive to understand the phenomena. Although the taste would be something that relates to the tongue, interestingly, the PI made a unique observation that TAS2R38 is being upregulated in multiple cancers, including CRC when mining The Cancer Genome Atlas (TCGA) database. Not too surprisingly, there are publications demonstrating upregulation of various receptors in lungs, ovary, prostate, and breast. In preliminary studies, we have determined that while there was no or little expression of TAS2R38 in normal colon and rectum tissues, it is significantly upregulated in human CRC tumor samples as well as in two mouse models, the azoxymethane (AOM)/dextran sulfate sodium (DSS) chemical carcinogenesis and the spontaneous APCmin mice. TAS2R38 is a G-protein coupled receptor, and using specific ligands we observed that it activates the calcium signaling pathway. Hence, to gain further insight into the function of the receptor, we will obtain fresh patient tissue samples and isolate primary cancer cells. Then we classify these cell lines based on low and high expression and perform RNA-sequencing to understand the changes in the global gene expression. Second, we will knock out the TAS2R38 gene so that the protein expression is lost and then evaluate t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110341
Entities
People
- Prasad Dandawate
Organizations
- United States Army
- University of Kansas Medical Center