Defining the Role of the Stromal Microenvironment in Early Serous Proliferations
Abstract
Rationale: High-grade serous carcinoma (HGSC) represents one of the most common and most deadly gynecologic malignancies. Like many cancers, HGSC is thought to arise from an early precursor lesion that subsequently undergoes transformation and eventually spreads throughout the body. Current evidence suggests that these precursor lesions arise on the surface lining of the distal fallopian tube and eventually escape from this surface through an undefined process. These precursor lesions are much more common than disseminated HGSC; thus, we rationalized that there must be additional molecular steps that are required for malignant transformation and spread. While some groups have focused on changes that occur specifically in the surface lining cells, we also rationalized that there may be crosstalk between the surface lining of the fallopian tube and the underlying stroma that these cells sit on and that this crosstalk may promote transformation and/or escape. This Pilot Award Proposal seeks to define the steps involved in early precursor formation and the role of the tumor microenvironment in promoting this transformation and early precursor escape. Critical Problem: HGSC is thought to develop from an early precursor lesion on the distal fallopian tube, yet it is estimated that only ~5% of these precursor lesions will subsequently go on to develop disseminated HGSC. HGSC often presents at a late stage and, unfortunately, there is currently no way to predict which of these precursor lesions will go on to transform. Defining the steps required for early transformation and for precursor escape is important for our basic understanding of the disease process as well as for proper stratification and treatment of patients. Patients whose precursor lesions are at high risk for transformation and spread may elect to undergo frequent surveillance and/or neoadjuvant treatment while patients with lesions at low risk for progression may elect for routine surveillance. Insights Gained: In contrast to existing models in the field, we hypothesize that there is crosstalk between the surface lining cells of the distal fallopian tube and the underlying stroma, including the immune cells, and that this crosstalk may be important for transformation and eventually escape and spread of the surface lining cells. By studying these two compartments together, we hope to further refine existing models and to identify new biological markers that could help risk stratify patients for follow-up. The new molecular markers we identify could also represent potential therapeutic targets that could allow us to block the transformation of early precursor lesions and/or their eventual escape. Relevance to Vision and Mission: Our proposed studies are directly relevant to the long-term vision and mission of the Congressionally Directed Medical Research Programs (CDMRP) to eliminate ovarian cancer. The goal of our project is to define the interactions that occur between precursor lesions on the fallopian tube and the microenvironment so that we can refine existing models. A second goal of the project is to identify new biological markers that can be used to appropriately risk-stratify patients. This is also aligned with the CDMRP’s goal of utilizing precision medicine to optimize patient care and outcomes. Innovation: There are two key innovative aspects to this Pilot Award Proposal: (1) a focus on the crosstalk between the surface lining cells and the underlying stroma and (2) the use of technology that allows us to look at these interactions while maintaining tissue architecture. Current models of early serous carcinogenesis focus on changes within the surface lining of the fallopian tube. While this is a likely source of HGSCs, these models ignore the crosstalk and potential contribution of the underlying stroma. Defining the role of the underlying stroma in early serous carcinogenesis is novel and could challenge existing mo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210128
Entities
People
- Walter Devine
Organizations
- United States Army
- University of California, San Francisco