Separate and not equal: sex differences in JAM-A tumor suppression in glioblastoma

See the article by Turaga et al. in this issue, pp. 1591–1601.

Glioblastoma (GBM) is an almost universally fatal primary brain tumor. Clinical incidence data demonstrate that GBM occurs in males at a higher rate and with a poorer overall prognosis.¹ Although prognostic differences among males and females have been well documented, only recently has research begun to shed light on the molecular mechanisms behind such differences in tumor growth and maintenance with regard to sex.^1–3 Yang and colleagues recently examined the mechanistic differences of GBM progression between males and females and concluded that because sex differences are seen in patients across all age brackets, hormone fluctuation throughout life is not likely to be the sole culprit.³ The authors discover that different signaling pathways may underlie the differences in survival between males and females, with females relying on integrin signaling and males on cell cycle regulation.³ This work sparked the need for a better understanding of biological and physiological mechanisms that underlie sex differences in GBM.

In the current study, Turaga and colleagues examine sex-driven mechanistic differences in junction adhesion molecule A (JAM-A), linked to cancer stem cell (CSC) maintenance in GBM.^4,5 Initially detected in GBM in 2014 as a highly expressed adhesion molecule enriched on CSCs, JAM-A has been shown to regulate CSC growth while not impacting the proliferation of normal neural stem cells.⁵ The original study demonstrates that JAM-A specifically promotes lamin-specific cell adhesion, and CSCs lacking JAM-A fail to adhere tumor extracellular matrix, which results in loss of cellular stemness.⁵ JAM-A has also subsequently been shown to have prognostic value in GBM as well as to be intricately tied to miR-145, a microRNA responsible for tumor suppression and CSC maintenance in GBM.^6,7 Turaga and colleagues now use this current study to build upon the previous JAM-A work and discover a previously unknown sex dependency in its functioning.

Utilizing the mouse glioma line GL261, the authors noted a difference in survival between male and female mice, which was subsequently reversed when examining mice deficient for JAM-A. Importantly, this difference was masked when groups were analyzed together, highlighting the importance of host microenvironment during gliomagenesis in a sex-specific manner. Building upon their previous work defining sex-specific differences in myeloid-derived suppressor cells in glioma,² the authors sought to categorize the tumor microenvironment in their mouse models and directly compare males and females. In doing so, they discovered that microglia deficient in JAM-A in female mice exhibit increased phagocytic properties. This phagocytic nature was also combined with microglia positive for ionized calcium binding adaptor molecule 1 in the female condition, indicating microglia activation. This microglia activation ultimately resulted in an anti-inflammatory and pro-tumorigenic microenvironment, leading to increased tumor proliferation. The sex-dependent contribution in GBM progression proposed by Turaga et al in this issue of Neuro-Oncology is particularly compelling because it is tumor cell extrinsic, focused on host involvement in establishing an oncogenic microenvironment.

Probing deeper, the authors hypothesize that estrogen may play a role in this response in female mice. By conducting ovariectomies across wild-type and JAM-A deficient mice, they discover that this results in more aggressive tumor types within the JAM-A deficient group but does not significantly impact the wild-type group, hinting at a possible protective effect of estrogen when JAM-A is lacking in female mice. Finally, the authors employ RNA sequencing analysis to probe further possible mechanistic underpinnings of the female JAM-A deficient tumor response. This leads to the discovery that JAM-A deficiency leads to a pro-tumorigenic microenvironment specifically by activation of FIZZ1 and Ifi202b. This in silico observation was further corroborated using JAM-A specific blocking antibodies which demonstrated induction of both FIZZ1 and Ifi202b in female microglia, ultimately changing microglial activation (Figure 1). The authors also establish that this microglial activation directly leads to the pro-tumorigenic gene signature and clinically reduced survival in females.

Fig. 1.

JAM-A has a sex-dependent role in GBM. JAM-A deficiency in females leads to microglia activation, enhances their phagocytic activity, and promotes GBM progression via FIZZ1 and Ifi202b expression. Figure created with BioRender.com

This timely study seeks to address a critically relevant gap in current GBM research: how sex difference can influence the tumor microenvironment and ultimately drive tumor progression and therapeutic resistance. While the current work lacks a viable drug target that could be translated to clinic, it directly establishes the value of probing differences in the tumor microenvironment resulting from sex. Sex differences due in part to hormone signaling are known to arise throughout the brain in synaptogenesis, dendritic spine development, and neurite outgrowth.⁸ This is highly relevant given that researchers have begun to demonstrate that GBM can functionally integrate into the brain surroundings through both electrical as well as neurochemical signaling.^9,10 These emerging interactions drive home GBM’s ability to interact with and manipulate its microenvironment rather than just passively grow within it. This is well demonstrated by Turaga and colleagues in the current study detailing that JAM-A signaling functions as a microenvironmental cue toward the tumor, somewhat like a neurotransmitter release or downstream electrical signal. However, a few important questions require further investigation. First, it is not clear how the activated microglia can promote GBM cell proliferation. If JAM-A involves establishing a feedback loop between microglia and GBM cells, then identifying such a pro-oncogenic signal would be critical to clinical target this pathway. Secondly, given the role of tumor-associated microglia in establishing the immunosuppressive microenvironment in GBM, it is conceivable that JAM-A signaling may influence the immune landscape of GBM in a sex-dependent manner. A comprehensive combination of the above works will be needed to properly elucidate if there are clinically meaningful sex-specific effects within the tumor microenvironment that can be taken advantage of to benefit patient survival.

In summary, the current study fits nicely into an emerging trend within the GBM field: demonstrating that not only are the tumors themselves cellularly complex but the microenvironments, and indeed the hosts as well, are just as complex. Further studies will no doubt continue to illuminate potentially relevant differences between male and female GBM tumor biology. Although the field has been striving to develop personalized therapeutics based on tumor biology, this has yet to be realized meaningfully in a clinical setting. Work highlighting sex differences in tumor biology could end up illuminating several new possible drug targets or therapeutic avenues able to extend the lives of patients. Indeed, in many other diseases, differences in sex play a pivotal role in how treatment paradigms are determined, and this may ultimately end up being the case for GBM. Furthermore, as important as it can be to find new therapeutics, these inherent sexual differences may illuminate therapies or strategies that do not work for patients’ cohorts due to differing biology based on sex. When it comes to further studies in GBM tumor biology, patient sex should be treated as separate and not equal.

Conflict of interest statement. The authors declare no competing financial interests.