A new study published in Neuro-Oncology and led by Justin Lathia, PhD, who co-directs the Center of Excellence in Brain Tumor Research and Therapeutic Development, offers novel biological insights into sex-based differences in glioblastoma, the most common primary malignant brain tumor.
To date, most sex-based differences in disease pathology have related to mechanisms that occur in cancer cells. “As we share in this paper, our group uncovered how activities in the tumor microenvironment—what we consider the non-cancer cell components of a tumor—drive glioblastoma progression differentially in male and female disease models,” said Dr. Lathia, Vice Chair of the Department of Cardiovascular & Metabolic Sciences.
These differences, they found, can be traced to the activity of a protein called JAM-A (junction adhesion molecule-A).
JAM-A’s activity in male versus female models
Dr. Lathia’s laboratory previously discovered that levels of JAM-A are highly elevated in glioma cancer stem cells (a particularly aggressive subset of cancer cells that can self-renew) and that levels of this molecule are associated with patient prognosis, where higher JAM-A levels predict worse outcomes. Others have shown that JAM-A is also highly expressed in cells within the tumor microenvironment, including microglia and macrophages (types of immune cells).
Here, in the team’s latest study, they identified that JAM-A suppresses the activity of microglia in female preclinical disease models. The researchers transplanted glioma cells into the brains of control and genetically engineered JAM-A-deficient preclinical models. “In comparing the brains of male and female models, we saw that microglia were more activated in the tumors of female JAM-A-deficient models than those of the female controls or either male groups,” explained Dr. Lathia. “In terms of the effect this had on glioblastoma progression, JAM-A deficiency led to hastened disease and shorter lifespan in female models.”
Microglia are innate immune cells that, through close connection with other cells and cell adhesion proteins, continually survey their surroundings in the central nervous system. When foreign pathogens or abnormal cells, like cancer cells, are detected, they help mount an immune response. In the context of glioblastoma, however, tumor cells alter the normally helpful anti-cancer behavior of microglia, turning them pro-tumorigenic.
Adding to a growing body of understanding of sex-based differences in glioblastoma
Taken together this suggests that in females, JAM-A suppresses microglial activation and subsequent anti-cancer immune response, which drives glioblastoma metastasis differently than in males. These findings offer critical insights that have the potential to, with more study, inform novel JAM-A-targeting and personalized glioblastoma treatment.
This will be important because while advancements have been made in recent years to better understand glioblastoma pathology and develop new therapies, much work is still left to be done as patient survival unfortunately remains relatively short following diagnosis. Part of this is due to the complexity and heterogeneity of glioblastoma-related brain changes, which vary from patient to patient.
“Ample research also suggests that disease burden and severity varies by sex, which adds to the complexity” said Dr. Lathia. “Our team is hopeful that our latest investigation will add to the field’s understanding of sex-based differences in glioblastoma, and reinforce that these sex-based differences extend to beyond just cancer cells.”
Soumya Turaga, PhD, who was a student in the Lathia laboratory, was first author on the study, which was done in collaboration with Dimitrios Davalos, PhD, Department of Neurosciences. Funding was provided in part by the National Institute of Neurological Disorders & Stroke (part of the National Institutes of Health), the American Brain Tumor Association and VeloSano (Cleveland Clinic’s flagship fundraising effort for cancer research).
This is the second study by Dr. Lathia’s group published in 2020 that shows a non-cancer cell role for sex differences in glioblastoma. In a paper published in Cancer Discovery, they found that subpopulations of myeloid-derived suppressor cells differ significantly between males and females with glioblastoma, and that they each contribute to disease pathology differently.
Image: Tumor sections from control (WT) and JAM-A deficient (KO) models stained with a microglia marker (green) to indicate microglia activation status.