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Caspase-8 is a cysteine protease that plays an essential role in apoptosis. Consistently with its canonical proapoptotic function, cancer cells may genetically or epigenetically downregulate its expression. Unexpectedly, Caspase-8 is often retained in cancer, suggesting the presence of alternative mechanisms that may be exploited by cancer cells to their own benefit. In this regard, we reported that Src tyrosine kinase, which is aberrantly activated in many tumors, promotes Caspase-8 phosphorylation on Tyrosine 380 (Y380) preventing its full activation. Here, we investigated the significance of Caspase-8 expression and of its phosphorylation on Y380 in glioblastoma, a brain tumor where both Caspase-8 expression and Src activity are often aberrantly upregulated. Transcriptomic analyses identified inflammatory response as a major target of Caspase-8, and in particular, NFκB signaling as one of the most affected pathways. More importantly, we could show that Src-dependent phosphorylation of Caspase-8 on Y380 drives the assembly of a multiprotein complex that triggers NFκB activation, thereby inducing the expression of inflammatory and pro-angiogenic factors. Remarkably, phosphorylation on Y380 sustains neoangiogenesis and resistance to radiotherapy. In summary, our work identifies a novel interplay between Src kinase and Caspase-8 that allows cancer cells to hijack Caspase-8 to sustain tumor growth.

In this study, Parisian et al. introduced an inducible SMARCB1 loss-of-function system into human iPSCs that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids to identify potential interactions between SMARCB1 loss and the process of neural development. Their findings provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.

The authors describe a usual case of infiltrative low-grade glial neoplasm with a marked enhanced area which is difficult to diagnose. A 42-year-old man had the diffuse mass lesion partially with apparent enhancement in the right temporal lobe, the insular, and the basal ganglia regions. Final pathological diagnosis from the removed specimens was IDH-wildtype diffuse astrocytomaaccording to 2016 WHO classification, although it had unusual findings including gliomesenchymal reaction. The nodule-like enhancement was thought to be owing to the mesenchymal component. Several molecular analysis including pyrosequence analysis, Ion Torrent™ next-generation sequencing and multiplex ligation-dependent probe amplification analysis detected no genomic abnormality. IDH-wildtype diffuse astrocytomais a heterogeneous category and has a minor subset with a silent genomic landscape like the present case.

The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.