# Project 3:  Sex-specific differences in the tumor microenvironment alter glioblastoma growth

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $375,603

## Abstract

PROJECT SUMMARY
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 neutral...

## Key facts

- **NIH application ID:** 10023716
- **Project number:** 1P01CA245705-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Justin D. Lathia
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,603
- **Award type:** 1
- **Project period:** 2020-09-14 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023716

## Citation

> US National Institutes of Health, RePORTER application 10023716, Project 3:  Sex-specific differences in the tumor microenvironment alter glioblastoma growth (1P01CA245705-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10023716. Licensed CC0.

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