Tubal Immune Milieu and Tumor Precursor Evolution in the Development of High-Grade Serous Carcinoma
Abstract
Hypothesis and Rationale for the Proposed Project: Women with germline mutations in BRCA1 and BRCA2 have increased lifetime risk of ovarian high grade serous carcinoma (HGSC). To date, there is no effective early HGSC screening method, and women with BRCA germline mutations are recommended to undergo risk-reducing salpingo-oophorectomy, a procedure which is often associated with long-term health consequences due to premature menopause. The early pathogenesis of HGSCs remains poorly understood, hampering our efforts to optimize screening and preventive strategies of HGSC. Our research data suggest that early serous proliferations (ESPs) in the fallopian tubes (FTs), which comprise TP53 mutant clones with nil to mild atypia, may act as early direct HGSC precursors. Understanding is extremely limited on the impact of the local immune microenvironment on the progression of these mutant clones. We previously sampled FTs from healthy women and women with tubal lesions as well as FTs from mouse models that developed HGSC, and showed in initial analyses that unique immune signatures in the FTs might differentially correlate with tubal pathology status. We hypothesize that (1) TP53-mutated FT epithelial lesions are associated with an increasingly proinflammatory immune phenotype and higher TP53 mutational pathogenicity as these FT lesions develop into malignancy, and (2) disruption of host immune response accelerates the progression of these lesions into carcinoma. In this proposed study, we will utilize multiplex immunofluorescence studies and RNA-based multiplex profiling to examine the local immune profiles in human and murine FTs with and without ESPs and FT HGSC, and evaluate the impact of immune cell depletion on clonal expansion and HGSC development in transgenic mouse models. Principle Investigator s Career Goals in Ovarian Cancer Research: I am a board-certified pathologist with expertise in gynecologic pathology and is fervently devoted to investigating the pathogenesis of ovarian cancer, particularly the prevention and detection of high-grade serous carcinoma (HGSC), which is the most common subtype and deadliest form of ovarian cancer. I had Ph.D. training in epidemiology, and subspecialized training in gynecologic pathology. My prior studies on ovarian cancer showed data supporting a novel paradigm for HGSC development, in which mutated cells could disseminate from FTs or clonally expand in the peritoneal cavity, which may give rise to carcinoma as direct precursors. The present study proposal is an expansion of my current research work and collaborations with co- investigators to further examine risk factors that promote the malignant transformation of these mutant clones. I have a track record of publications and short-term independent funding in ovarian cancer research. My long-term career goal is to become an independent clinician-scientist and establish an integrative molecular, pathological and epidemiologic research program to study the interactions between the local microenvironment and host exposures in the setting of HGSC. The aim is to identify factors influencing the development of HGSC, with translation of findings to population-based studies to inform better strategies for HGSC prevention and detection. I believe my rare combination of training backgrounds in pathology and epidemiology would contribute to the diversity of expertise and perspectives in the ovarian cancer research community. The proposed research and the early-investigator award will provide me with the perfect venue to acquire the necessary training, mentorship and funding to achieve my career goal while addressing a critical question in the pathogenesis and early detection of HGSC. Applicability of the Research Study: The proposed research study is based on a novel paradigm uniting the host immune milieu with TP53 clonal evolution in the FTs and addresses the understudied question on how the local immune microenv
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310442
Entities
People
- T. Rinda Soong
Organizations
- United States Army