Anastasiadis, Pavlos

Abstract Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.

Abstract Background Fibroblast growth factor-inducible 14 (Fn14) belongs to the TNFR superfamily. Fn14 overexpression can drive receptor-autonomous signaling, increase both cell invasion and tumor-associated macrophages/microglia (TAMMs) recruitment, and correlates with reduced survival in glioblastoma (GBM) patients and rat gliomas. While prior studies report Fn14 expression in non-tumor cells within the GBM tumor microenvironment (TME), their relative contributions to glioma pathobiology remain unclear. Methods Using tumor-host pairings of Fn14-positive and -knockout (-KO) cells and mice, we examined the role of Fn14 in glioma biology. Mouse glioma and human GBM datasets were analyzed at the cellular, protein, and transcriptomic levels to assess Fn14-associated changes in the glioma TME and survival outcomes. Results Fn14 was found to be highly expressed in tumor cells and TAMMs in human GBM and 2 well-characterized murine glioma models. Fn14 KO in both tumor and host cells increased overall survival. Notably, this survival benefit was greater in the glioma model characterized by a more immunologically activated TME. Immunophenotyping revealed that Fn14 loss reshapes the tumor-immune landscape, reducing the presence of immunosuppressive macrophages and exhausted T-cells, suggesting that Fn14 modulates both innate and adaptive immune responses. These findings were supported by analyses of human GBM datasets, where high Fn14 expression correlated with immunosuppressive shifts and poor patient responses to immune checkpoint inhibitor therapy. Conclusions This study provides the first description of the contributions of both tumor- and host-derived Fn14 expression to tumor immunity and survival and identifies Fn14 as an important mediator of innate and adaptive immune responses in gliomas.

Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment ofGBMincluding the tightly controlled interface between the bloodstream and central nervous system termed the ‘neurovascular unit,’ a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal ofGBMtherapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified asGBMtargets include the transferrin receptor, low‐density lipoprotein receptor‐related protein, αvβ3integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR),EGFRvariantIII, interleukin‐13 receptor α chain variant 2, and fibroblast growth factor‐inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (1) adhesive interactions with nontarget structures, (2) low density or prevalence of the target, (3) lack of target specificity, and (4) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the keyGBMtargets with the goal of advancing the understanding and development of targeted nanotherapeutics forGBM.WIREs Nanomed Nanobiotechnol2017, 9:e1439. doi: 10.1002/wnan.1439This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging TechnologiesTherapeutic Approaches and Drug Discovery > Nanomedicine for Neurological DiseaseTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease