Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.

Soluble ACE2 (sACE2) decoys are promising agents to inhibit SARS‐CoV‐2, as their efficiency is unlikely to be affected by escape mutations. However, their success is limited by their relatively poor potency. To address this challenge, multimeric sACE2 consisting of SunTag or MoonTag systems is developed. These systems are extremely effective in neutralizing SARS‐CoV‐2 in pseudoviral systems and in clinical isolates, perform better than the dimeric or trimeric sACE2, and exhibit greater than 100‐fold neutralization efficiency, compared to monomeric sACE2. SunTag or MoonTag fused to a more potent sACE2 (v1) achieves a sub‐nanomolar IC50, comparable with clinical monoclonal antibodies. Pseudoviruses bearing mutations for variants of concern, including delta and omicron, are also neutralized efficiently with multimeric sACE2. Finally, therapeutic treatment of sACE2(v1)‐MoonTag provides protection against SARS‐CoV‐2 infection in an in vivo mouse model. Therefore, highly potent multimeric sACE2 may offer a promising treatment approach against SARS‐CoV‐2 infections.

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Soluble ACE2 (sACE2) decoy receptors are promising agents to inhibit SARS-CoV-2 as they are not affected by common escape mutations in viral proteins. However, their success may be limited by their relatively poor potency. To address these challenges, we developed a highly active multimeric sACE2 decoy receptor via a SunTag system that could neutralize both pseudoviruses bearing SARS-CoV-2 spike protein and SARS-CoV-2 clinical isolates. This fusion protein demonstrated a neutralization efficiency nearly 250-fold greater than monomeric sACE2. SunTag in combination with a more potent version of sACE2 achieved near complete neutralization at a sub-nanomolar range, which is comparable with clinical monoclonal antibodies. We demonstrate that this activity is due to greater occupancy of the multimeric decoy receptors on Spike protein as compared to monomeric sACE2. Overall, these highly potent multimeric sACE2 decoy receptors offer a promising treatment approach against SARS-CoV-2 infections including its novel variants.

Glioblastoma is the most common type of primary brain tumor with an aggressive clinical course, and one of the cornerstones in its treatment regimen is radiotherapy. However, tumor cells surviving after radiation is an indicator of treatment failure; therefore, better understanding of the molecular mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated multiple clinically relevant irradiation exposed models, where we applied fractionated radiotherapy over a long period of time and selected irradiation-survivor (IR-Surv) glioblastoma cell populations. In these cells, we examined the transcriptomic alterations, cell cycle and growth rate changes as well as responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Transcriptomic analysis revealed that IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, MGMT, and had better DNA repair capacity as an adaptive mechanism. Separately, we report IR-Surv cells to display downregulation of hypoxic signature and the lower induction of hypoxia target genes and not exhibiting the same level of hypoxia-induced changes with naive glioblastoma cells, as gauged by exposing cells to different hypoxia conditions. We also showed that Chk1 inhibition alone or in combination with irradiation significantly reduces cell viability in both naive and IR-Surv cells. However, IR-Surv cells were markedly less sensitive to Chk1 inhibition under hypoxic conditions. In conclusion, consistent with previous reports, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naive and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions. Thus, our findings with clinically relevant radiation survivor models will have future translational implications and benefit the optimization of combination therapies for glioblastoma patients.