Abstract Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a “matrix code” for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better patient survival, respectively. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles provide potential biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification which could be applied to optimize treatment responses.
TWIST is a basic helix-loop-helix (bHLH) transcription factor that regulates mesodermal development, promotes tumor cell metastasis, and, in response to cytotoxic stress, enhances cell survival. Our screen for bHLH gene expression in rat C6 glioma revealed TWIST. To delineate a possible oncogenic role for TWIST in the human central nervous system (CNS), we analyzed TWIST message, protein expression in gliomas, normal brain. TWIST was detected in the large majority of human glioma-derived cell lines, human gliomas examined. Increased TWIST mRNA levels were associated with the highest grade gliomas, increased TWIST expression accompanied transition from low grade to high grade in vivo, suggesting a role for TWIST in promoting malignant progression. In accord, elevated TWIST mRNA abundance preceded the spontaneous malignant transformation of cultured mouse astrocytes hemizygous for p53. Overexpression of TWIST protein in a human glioma cell line significantly enhanced tumor cell invasion, a hallmark of high-grade gliomas. These findings support roles for TWIST both in early glial tumorigenesis, subsequent malignant progression. TWIST was also expressed in embryonic, fetal human brain, in neurons, but not glia, of mature brain, indicating that, in gliomas, TWIST may promote the functions also critical for CNS development or normal neuronal physiology.
High-grade (World Health Organization [WHO] Grade II and III) meningiomas constitute a minority of all meningioma cases but are associated with significant morbidity and mortality, due to more aggressive tumor behavior and a tendency to recur despite standard therapy with resection and radiotherapy. They display a higher degree of vascularity than WHO Grade I meningiomas and produce angiogenic and growth factors, including vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF-A, has been used in the treatment of recurrent or progressive meningiomas resistant to standard therapy. We report a patient with a recurrent left frontotemporal meningioma and associated-vision loss who experienced substantial visual field recovery after 3 cycles of bevacizumab. In addition, we provide a review of the literature regarding the efficacy of bevacizumab in the treatment of recurrent meningiomas.
Introduction: Neurotropism of the SARS-CoV-2 has been reported. We evaluated the risk of poor outcomes associated with preexisting neurological disease (PEND) among COVID-19 patients. Methods: We analyzed data from COVID-19 Outcomes Registry (CURATOR) at Houston Methodist. All adult (≥ 18 years) patients tested for SARS-CoV-2 RNA in nasopharyngeal specimens were included. Utilizing ICD-10 diagnoses codes, we classified PEND patients as those with documented history of ischemic or hemorrhagic stroke, transient ischemic attack, mild cognitive impairment, Alzheimer’s disease and related dementias including vascular dementia, primary and metastatic brain tumors, epilepsy, motor neuron disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, spinal cord injury, and traumatic brain injury. Logistic regression models were fitted to assess the odds of COVID-19 mortality associated with PEND. Odds ratios (OR) and 95% Confidence Intervals (CI) are reported. Results: Between March 3 and August 10, 2020, 86,614 individuals were tested for SARS-CoV-2, of whom 14,233 (16.4%) tested positive, with 4,473 (31.4%) hospitalizations, and 431 (9.6%) deaths. Overall 11,473 (13.2%) individuals had PEND, of whom 1,458 (12.7%) tested positive, 966 (66.3%) were hospitalized and 165 (17.1%) died. Among positive cases, PEND (vs. non-PEND) patients were older (67.1 vs. 46.4 years) and had a higher overall comorbidity burden (median Charlson Comorbidity Index: 6 vs. 1). The proportion of PEND patients was significantly higher among COVID-19 patients who died (vs. those who were discharged alive) (38.3% vs. 19.8%, crude OR, CI: 2.51, 2.03 - 3.09). In the fully adjusted model for socio-demographic, comorbidity and clinical factors, PEND was independently associated with higher risk of COVID-19 mortality OR (CI): 1.42 (1.04, 1.95) (graphic). Conclusions: Biological mechanisms of higher COVID-19 mortality among patients with PEND need to be evaluated.
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