Collagen Variants Sensitize Stomach Tumors to Therapeutics
Abstract
This proposal focuses on the Topic Area of stomach cancer and the Military Relevance Focus area of improving prognosis and treatment. The goal of this proposal is to test the novel hypothesis that mutations in collagens mediate the tumor environment and to develop novel therapeutics targeting the chemoresistant, wild-type collagen tumor environment. The tumor microenvironment is a crucial determinant of patient outcome dictating disease aggression and chemoresponse. The proposed research will reveal new insight into the loss of function of collagen mutations and their potential role in tumor dissemination and drug resistance, based on patient samples and preclinical models. This study will improve prognosis by developing somatic collagen mutations as prognostic markers. Together, the evaluation of the impact of collagen mutations on gastric tumors in patients and mechanistic studies in preclinical models will demonstrate the role of collagen mutations in gastric cancer, motivate the development of mutant collagen-based therapeutics and repurpose drugs to target tumors with COL7A1 expression. Collagens are the most abundant protein in the body, most famous perhaps, for their role in wrinkled skin during aging with collagen type I. Many collagens not typically expressed in the tissue of origin are highly expressed in tumors and become critical components of the tumor environment. The presence of collagens has been associated with poor outcomes in patients with solid tumors, including stomach cancers. Collagens direct many of the seminal hallmarks of cancer including cell movement and resistance to treatment. So-called “minor” collagens, which are typically expressed specifically in normal tissues, have not been systematically investigated in gastric tumors. We have found that collagens, especially minor collagens, such as type VII, are frequently mutated in tumors. These mutations resemble the same types of mutations in collagens that cause collagenopathies, which are inherited diseases that disrupt tissues such as skin and cartilage, leading to severe and painful consequences for patients. We hypothesize that collagen mutants, originating in cancer cells, disrupt the tumor environment and sensitize tumors to treatment, leading to better outcomes for stomach cancer patients. Conversely, tumors that express these minor collagens without mutation define a class of tumors that are chemoresistant and lead to high risk of shorter overall survival. Therefore, we hypothesize that these minor collagens enhance targetable specific pathways that cause a chemoresistant tumor state. Our computational findings predict which pathways and drugs to be repurposed to target this class of difficult to treat tumors. We propose to focus on collagen type VII, which is one of the collagens with mutations most strongly associated with longer survival in gastric cancer patients and has been extensively studied as the cause of Dystrophic Epidermolysis Bullosa (DEB). We observe the same type of COL7A1 mutations in gastric tumors that cause DEB. We will test the impact of these mutations COL7A1 on gastric cancer cells by engineering cells to make the mutant form and test the effects on cancer cell properties in pre-clinical models, including response to drugs. To achieve these goals, we will use standard and develop novel models to study the impact of minor collagens in cancer. We will identify pathways and drugs to overcome resistance in tumors that express non-mutated COL7A1 guided by the bioinformatic predictions in combination with screening. Exposure to chemical/infectious hazards by military members can contribute to cancer formation. Stomach cancer can be caused by exposure to infectious agents, leading to high rates in the non-developed world, where many military personnel are stationed. Military personnel stationed around the world may be exposed to agents that can have long-term consequences, leading to stomach cancer requirin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010476
Entities
People
- Alexander Brodsky
Organizations
- Rhode Island Hospital
- United States Army