The Role of Bitter Taste Receptor TAS2R38 in Esophageal Cancer
Abstract
Scientific Objective and Rationale: Esophageal Cancer (EC) is the seventh leading cause of cancer-related deaths in the U.S. and are projected to increase 35% by 2025, with a poor survival rate of less than 20%. Esophageal adenocarcinoma (EAC) is less studied compared to other cancers, and it typically shows extremely aggressive clinical features if diagnosed late, making it an extremely difficult cancer to treat. Three main causes for EAC increases are excess body weight, a high-fat diet, and an increased number of cases of Barrett s esophagus (BE), a precancerous condition for EAC. While studying the taste changes in patients with BE and gastrointestinal acid reflux disease (GERD), we unexpectedly discovered one of the taste receptors responsible for recognizing bitter taste is highly expressed in EAC patients. Patient Investigators with Voices Together (PIVOT) is an organization within the cancer center where individuals with lived cancer experience (as a survivor or caregiver) periodically connect with investigators to discuss various bedside observations. It was during one of these meetings at which the Principal Investigator (PI) heard from a patient experiencing bitter taste prior to their cancer diagnosis. This led the drive to understand the phenomena. Although the taste would be something that relates to the tongue, interestingly, the PI made a unique observation that bitter taste receptor type 2 member 38 (TAS2R38) is being upregulated (44-fold) in EC when mining The Cancer Genome Atlas database. Our research confirmed TAS2R38 is highly expressed in EAC tissues and cell lines compared to normal tissues. Further, we treated EAC cell lines with a specific compound N-(3-oxododecanoyl)-L-homoserine lactone that selectively binds to TAS2R38, and we observed a calcium release in the cells suggesting the TAS2R38 receptor is functional in EAC. The objective of our study is to understand the role of TAS2R38 in EAC progression and as an early marker for EAC. What Types of Patients Will the Research Help and How Will It Help Them? EAC biology is not extensively studied, and diagnosis and treatment strategies have not been developed. There are differences in EAC incidence and survival outcomes based on race and gender. African American (AA) population is reported to have a higher death rate as compared to Caucasians. Esophageal squamous cell carcinoma has been commonly diagnosed in AA and Caucasian females, whereas esophageal adenocarcinoma is more common among Caucasian males in the U.S. We found that TAS2R38 expression is high in the AA population compared to Caucasians and high in males compared to females. Hence, we believe TAS2R38 might serve as a biomarker to explain these racial and gender differences. Also, Kansas City hospitals provide treatment for patients living in rural areas. Traveling far to receive treatment acts as a barrier and is an under-recognized problem. We will include BE and EAC patient populations from different geographical locations, races, gender to establish TAS2R38 as a novel biomarker for early detection. Further, we will study the role of TAS2R38 in EAC progression, which will serve as a foundation for developing future studies for prevention and therapy of EAC in Veterans, their Families, underserved, underrecognized and the general population. FY22 PRCRP Overarching Challenge(s): The research proposed in this proposal will establish TAS2R38 is a novel biomarker to predict EAC risk and advancement of the disease in active-duty Service Members, Veterans, and the American public. We will use a larger cohort of Veteran patients from different races, gender, and geographical locations to study the TAS2R38 expression. We will use patient-derived cell lines and cutting-edge technologies such as single-cell RNA sequencing and proteomics to help us study the role of TAS2R38 signaling in EAC in an unbiased manner. We will also delete TAS2R38 from cell lines to study the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310391
Entities
People
- Prasad Dandawate
Organizations
- United States Army
- University of Kansas Medical Center