Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and continues to progress despite aggressive therapies including surgery, radiation, and chemotherapy. The interaction between tumor cells and their surrounding microenvironment directly impacts their growth and resistance to conventional therapies. We have had a long-standing interest in the mechanisms responsible for cellular interactions in the context of cancer stem cells (CSCs) and previously identified a pro-tumiogenic function for junctional adhesion molecule- A (JAM-A) in CSC maintenance. To test the function of JAM-A in the tumor microenvironment, we utilized JAM-A knockout mice to assess the growth of syngeneic mouse glioma cells. We found sex-specific differences in survival, with female knockout mice having more aggressive tumors, suggesting that JAM-A functioned as a tumor suppressor in the female microenvironment. Additional assessments revealed an increase in the number and activation status microglia, the native immune cells of the brain, and lipocalin 2 (LCN2) signaling in the female JAM-A knockout mice, highlighting an underlying sex-specific difference in the function of JAM-A in the tumor microenvironment. These findings serve as the basis for this project to further interrogate this newly identified, sex-specific difference in JAM-A in the tumor microenvironment in the context of a larger Program Project application on sex differences in GBM. The translational goal of this project is to conduct mechanistic studies on the sex-specific function of JAM-A in immune cells in the tumor microenvironment. This will be achieved using a combination of genetic mouse models, syngeneic mouse glioma models, and a high-resolution assessments of immune cells in the tumor microenvironment and in vivo imaging platform, with validation in human tissue. We hypothesize that JAM-A functions as a female microenvironment tumor suppressor by reducing microglial and immune activation and LCN2 signaling.
Aim 1 will test the hypothesis that JAM-A functions as a tumor suppressor in females via differential microglia activation and tumor-host interactions.
Aim 2 will test the hypothesis that LCN2 in the GBM microenvironment enhances tumor cellular iron uptake and can be targeted to attenuate tumor growth and invasion in a sex-specific manner. The long-term goal of this project is to identify the function of JAM-A in the GBM microenvironment and pinpoint specific mechanisms that can be leveraged to reduce GBM growth for sex-specific personalized medicine approaches. This project integrates with Project 1 and Project 2 of this P01 and will be enhanced by the cores. Results from this project will impact Project 1 by providing an opportunity to determine whether cell intrinsic or extrinsic sex differences are the dominant contributor to tumor growth and dispersion and will impact Project 2 by determining how sex-specific immune cell differences can synergize with or neutralize iron metabolism.
Cellular interactions between tumor cells and their surrounding microenvironment enhance therapeutic resistance, the stem cell program, and tumor growth, and we previously identified a cancer stem cell-specific adhesion mechanism, junctional adhesion molecule-A (JAM-A), that drives glioblastoma (GBM) growth. In this project, we will focus on the role of JAM-A in the tumor microenvironment, namely microglia, which also express JAM-A, and test the hypothesis that JAM-A functions as a tumor suppressor in the female microenvironment. The successful completion of this proposal will demonstrate a sex-specific the role of JAM- A in the tumor microenvironment, delineate a female-specific signaling axis that suppresses tumor growth, highlight a sex-specific mechanism of the GBM microenvironment, and integrate with the other projects in this Program Project application.
