Neoplasia-Derived Extracellular Vesicle microRNAs Cause DNA Damage to Promote Carcinogenesis in Barrett Esophagus: Novel Targets for Chemical Ablation
Abstract
Our proposal addresses the fiscal year 2021 Peer Reviewed Cancer Research Program Topic Area of esophageal cancer focusing on esophageal adenocarcinoma (EAC). This lethal malignancy has affected approximately 8,000 Veterans over the last decade, 85% of whom died within 2 years of the diagnosis. EAC develops from Barrett’s esophagus (BE), the condition in which the normal squamous lining of the esophagus is replaced by a metaplastic intestinal-type lining. Other risk factors for EAC are gastroesophageal reflux disease (GERD), obesity, and smoking, all of which are inordinately common conditions in Veteran patients. The prognosis for patients with EAC is strongly related to cancer stage at the time of diagnosis. The overall mean 5-year survival rate for EAC is a dismal 18%, but exceeds 80% for those with early cancers. Early cancers arising from BE can be treated with an endoscopic procedure that resects the cancer followed by radiofrequency ablation (RFA), an endoscopic procedure that burns away the cancer-prone metaplastic BE lining. However, RFA is fraught with complications, and early cancer recurs in 15% of patients. Thus, a better way to destroy Barrett’s cells surrounding an early cancer is needed. Our proposal will test a new idea that exploits the presence of DNA damage within BE cells surrounding the cancer. Intact DNA is necessary for healthy cells, but when DNA is damaged cells can progress to cancer. However, this DNA damage makes the cells more vulnerable to treatments that selectively attack those cells. Our preliminary experiments demonstrate that EAC cancer cell lines release small vesicles termed extracellular vesicles (EV) that contain molecular cargo that signals to surrounding BE cells, causing DNA damage through a process called minority mitochondrial outer membrane permeabilization (MOMP). Ordinarily, cells repair DNA damage via homologous recombination (HR), but this pathway is also disrupted in the BE cells exposed to EAC EV. Long-term accumulation of such DNA damage can eventually result in cancer development of those BE cells. We found that the molecular cargo of the EAC EVs might be microRNAs, small fragments of genomic material that inhibit the expression of genes involved in MOMP and HR. Using blood from Veteran patients with EAC, we isolated EV from the blood and found that they contain a number of microRNAs that are similar to those found in the EAC cancer cell EVs, and that they caused DNA damage in BE cells while inhibiting its repair. To stop BE cells with DNA damage from becoming cancer, we can use a new cancer drug that inhibits a molecule called PARP, which BE cells with DNA damage need to survive. If we inhibit PARP, then DNA damage in the BE cell worsens to a point that kills them. Our proposal aims to understand the molecular events of how DNA damage occurs in BE cells exposed to EAC EV and if inhibiting PARP can selectively kill those BE cells at the highest risk of developing cancer. Thus, we hypothesize that microRNAs within neoplasia-derived EV initiate minority MOMP and inhibit HR, mechanisms that promote neoplastic progression of benign BE cells by causing DNA damage while blocking its repair. The aims of this study are to elucidate how BE neoplasia-derived EV cause DNA damage and impede DNA damage repair of benign BE cells and promote their neoplastic progression and to assess the potential of inhibitors of PARP to ablate BE surrounding a nidus of neoplasia. Instead of using RFA, which indiscriminately kills BE cells as well as normal cells in the esophagus and causes a number of complications, our results will help determine if PARP inhibition is a viable therapeutic approach. Our ultimate goal is to develop tailored treatments to selectively kill BE cells at high risk for cancer progression, thus stemming the rising incidence of EAC in our Veterans and preventing EAC-related deaths among Veterans and non-Veterans with BE.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310385
Entities
People
- Ajay Bansal
Organizations
- United States Army
- University of Kansas Medical Center