Tyrel Porter¹, Ciro M. Carrillo Marcano¹, Miguel Mayol del Valle², Lilia Kucheryavykh¹

¹Department of Biochemistry, Universidad Central del Caribe, Bayamón, PR 00956, USA

²Department of Neurosurgery, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00921, USA

Introduction: Glioblastoma, considered to be the most aggressive form of brain cancer in adults, exhibits sex-dependent differences in both incidence and clinical outcomes. Our previous studies demonstrated a positive relationship between the activation of a proline-rich non-receptor tyrosine kinase and focal adhesion kinase, commonly known as Pyk2 and FAK respectively, signaling in glioblastoma cells and the expression of cytokines by tumor-associated myeloid cells. This study scrutinizes sex-dependent factors in tumor-associated myeloid cytokines’ influence on Pyk2 and FAK signaling activation in glioblastoma.

Methods: 21 specimens from clinical samples were processed to isolate glioblastoma and tumor-associated myeloid cells through percoll gradients. RT-PCR was subsequently used to evaluate the cytokines expression levels as well as Pyk2 and FAK in glioma cell fraction. Phosphorylation levels of Pyk2(Y579/580) and FAK(Y925) were evaluated by western blotting.

Results: A Pierson correlation analysis demonstrated positive correlations (r=0.9) between microglia/macrophages marker CD11b in tumor and the proportion of phosphorylated FAK expression in glioblastoma cells in males, but not in females. A strong correlation (r>0.85) between both Pyk2 and FAK phosphorylation levels in glioblastoma cells and gene expression of PDGFα, PDGFβ, IL-8, and CXCL12 in TAMs, with the additional correlation between Pyk2 phosphorylation and IL6 and IL10 expression were evident in male patients. Contrarily, the positive correlation between Pyk2 and FAK phosphorylation levels and IL6, IL8, IL10, and CXCL12 expression were detected in females.

Conclusion: These findings suggest nuanced sex-dependent regulatory mechanisms of Pyk2 and FAK signaling in glioblastoma, mediated by tumor-associated myeloid cytokines, underscoring the need for a more comprehensive mechanistic exploration. Future research into these mechanisms has potential implications for tailored therapeutic strategies for both male and female patients, highlighting sex-specific factors’ role in glioblastoma pathogenesis.

Acknowledgements: This study was supported by NIH Grant 1SC1GM122691.