Sorting nexin 10 sustains PDGF receptor signaling in glioblastoma stem cells via endosomal protein sorting.

Glioblastoma is the most malignant primary brain tumor, the prognosis of which remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared with NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor ß (PDGFRß) proliferative and stem cell signaling pathways through posttranscriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft-bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment.

Can a bioactive interbody device reduce the cost burden of achieving lateral lumbar fusion?

OBJECTIVE: Intervertebral devices are increasingly utilized for fusion in the lumbar spine, along with a variety of bone graft materials. These various grafting materials often have substantial cost burdens for the surgical procedure, although they are necessary to overcome the limitations in healing capacity for many traditional interbody devices. The use of bioactive interbody fusion devices, which have demonstrable stimulatory capacity for the surrounding osteoblasts and osteoprogenitor cells and allow for osseointegration, may reduce this heavy reliance on osteobiologics for achieving interbody fusion. The objective of this study was to evaluate the rate of successful interbody fusion with a bioactive lateral lumbar interbody titanium implant with limited volume and low-cost graft material. METHODS: The authors conducted a retrospective study (May 2017 to October 2018) of consecutively performed lateral lumbar interbody fusions with a bioactive 3D-printed porous titanium interbody device. Each interbody device was filled with 2-3 cm3/cage of a commercially available ceramic bone extender (ß-tricalcium phosphate-hydroxyapatite) and combined with posterior pedicle screw fixation. No other biological agents or grafts were utilized. Demographic, clinical, and radiographic variables were captured. Fusion success was the primary endpoint of the study, with graft subsidence, fixation failure, and patient-reported outcomes (Oswestry Disability Index [ODI] and visual analog scale [VAS]-back and -leg pain scores) collected as secondary endpoints. The authors utilized a CT-based fusion classification system that accounted for both intervertebral through-growth (bone bridging) and ingrowth (integration of bone at the endplate-implant interface). RESULTS: In total, 136 lumbar levels were treated in 90 patients. The mean age was 69 years, and 63% of the included patients were female. Half (50.0%) had undergone previous spinal surgery, and a third (33.7%) had undergone prior lumbar fusion. A third (33.7%) were treated at multiple levels (mean levels per patient 1.51). One year after surgery, the mean improvements in patient-reported outcomes (vs preoperative scores) were -17.8 for ODI (p < 0.0001), -3.1 for VAS-back pain (p < 0.0001), and -2.9 for VAS-leg pain (p < 0.0001). Bone bridging and/or appositional integrity was achieved in 99.3% of patients, including 97.8% who had complete bone bridging. No fixation loosening or implant failure was observed at any segment. Low-grade graft subsidence (Marchi grade ≤ I) occurred in 3 levels (2.2%), and intraoperative endplate violation occurred twice (1.5%). High-grade subsidence was not found. No implant failure or revision surgery for pseudarthrosis/subsidence was necessary. CONCLUSIONS: The use of bioactive titanium interbody devices with a large surface footprint appears to result in a very high rate of effective fusion, despite the use of a small volume of low-cost biological material. This potential change in the osteobiologics required to achieve high fusion rates may have a substantially beneficial impact on the economic burden inherent to spinal fusion.

CDK 4/6 inhibitors for the treatment of meningioma.

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use.

Racial and ethnic disparities in brain tumour survival by age group and tumour type.

PURPOSE: The extent to which racial/ethnic brain tumour survival disparities vary by age is not very clear. In this study, we assess racial/ethnic brain tumour survival disparities overall by age group and type. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) 18 registries for US-based individuals diagnosed with a first primary malignant tumour from 2007 through 2016. Cox proportional hazards regression was used to compute adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between race/ethnicity and brain tumour survival, stratified by age group and tumour type. RESULTS: After adjusting for sex, socioeconomic status, insurance status, and tumour type, non-Hispanic (NH) Blacks (HR: 1.26; 95% CI: 1.02-1.55), NH Asian or Pacific Islanders (HR: 1.29; 95% CI: 1.01-1.66), and Hispanics (any race) (HR: 1.28; 95% CI: 1.09-1.51) all showed a survival disadvantage compared with NH Whites for the youngest age group studied (0-9 years). Furthermore, NH Blacks (HR: 0.88; 95% CI: 0.91-0.97), NH Asian or Pacific Islanders (HR: 0.84; 95% CI: 0.77-0.92), and Hispanics (any race) (HR: 0.91; 95% CI: 0.85-0.97) all showed a survival advantage compared with NH Whites for the 60-79 age group. Tests for interactions showed significant trends, indicating that racial/ethnic survival disparities disappear and even reverse for older age groups (P < 0.001). This reversal appears to be driven by poor glioblastoma survival among NH Whites (P < 0.001). CONCLUSION: Disparities in brain tumour survival among minorities exist primarily among children and adolescents. NH White adults show worse survival than their minority counterparts, which is possibly driven by poor glioblastoma biology.

Glioblastoma stem cells reprogram chromatin in vivo to generate selective therapeutic dependencies on DPY30 and phosphodiesterases.

Glioblastomas are universally fatal cancers and contain self-renewing glioblastoma stem cells (GSCs) that initiate tumors. Traditional anticancer drug discovery based on in vitro cultures tends to identify targets with poor therapeutic indices and fails to accurately model the effects of the tumor microenvironment. Here, leveraging in vivo genetic screening, we identified the histone H3 lysine 4 trimethylation (H3K4me3) regulator DPY30 (Dpy-30 histone methyltransferase complex regulatory subunit) as an in vivo­specific glioblastoma dependency. On the basis of the hypothesis that in vivo epigenetic regulation may define critical GSC dependencies, we interrogated active chromatin landscapes of GSCs derived from intracranial patient-derived xenografts (PDXs) and cell culture through H3K4me3 chromatin immunoprecipitation and transcriptome analyses. Intracranial-specific genes marked by H3K4me3 included FOS, NFκB, and phosphodiesterase (PDE) family members. In intracranial PDX tumors, DPY30 regulated angiogenesis and hypoxia pathways in an H3K4me3-dependent manner but was dispensable in vitro in cultured GSCs. PDE4B was a key downstream effector of DPY30, and the PDE4 inhibitor rolipram preferentially targeted DPY30-expressing cells and impaired PDX tumor growth in mice without affecting tumor cells cultured in vitro. Collectively, the MLL/SET1 (mixed lineage leukemia/SET domain-containing 1, histone lysine methyltransferase) complex member DPY30 selectively regulates H3K4me3 modification on genes critical to support angiogenesis and tumor growth in vivo, suggesting the DPY30-PDE4B axis as a specific therapeutic target in glioblastoma.

Traumatic rupture of thoracic epidural capillary hemangioma resulting in acute neurologic deficit: illustrative case.

BACKGROUND: Thoracic epidural capillary hemangioma is exceedingly rare, with only a few reported cases. The typical presentation usually includes chronic, progressive symptoms of spinal cord compression in middle-aged adults. To the authors' knowledge, this case is the first report in the literature of acute traumatic capillary hemangioma rupture. OBSERVATIONS: A 22-year-old male presented with worsening lower extremity weakness and paresthesias after a fall onto his spine. Imaging showed no evidence of spinal fracture but revealed an expanding hematoma over 24 hours. Removal of the lesion demonstrated a ruptured capillary hemangioma. LESSONS: This unique case highlights a rare occurrence of traumatic rupture of a previously unknown asymptomatic thoracic capillary hemangioma in a young adult.

The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells.

Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSC). Here, we interrogated N 6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA immunoprecipitation followed by sequencing and transcriptome analysis, finding transcripts marked by m6A often upregulated compared with normal neural stem cells (NSC). Interrogating m6A regulators, GSCs displayed preferential expression, as well as in vitro and in vivo dependency, of the m6A reader YTHDF2, in contrast to NSCs. Although YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized MYC and VEGFA transcripts in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2-MYC axis in GSCs. The IGF1/IGF1R inhibitor linsitinib preferentially targeted YTHDF2-expressing cells, inhibiting GSC viability without affecting NSCs and impairing in vivo glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2-MYC-IGFBP3 axis as a specific and novel therapeutic target in glioblastoma. SIGNIFICANCE: Epitranscriptomics promotes cellular heterogeneity in cancer. RNA m6A landscapes of cancer and NSCs identified cell type-specific dependencies and therapeutic vulnerabilities. The m6A reader YTHDF2 stabilized MYC mRNA specifically in cancer stem cells. Given the challenge of targeting MYC, YTHDF2 presents a therapeutic target to perturb MYC signaling in glioblastoma.This article is highlighted in the In This Issue feature, p. 211.

Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions.

Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment.

Epigenetic N6-methyladenosine modification of RNA and DNA regulates cancer.

The biological roles of N6 methylation of nucleic acids have been extensively studied. Adenine methylation of RNA is the most prevalent RNA modification and has widespread effects on RNA splicing, translation, localization, and stability. Aberrant dynamic regulation of RNA N6-methyladenosine (m6A) has been reported in numerous human diseases, including several cancers. In recent years, eukaryotic DNA N6-methyladenosine (6mA) has also been reported and implicated in cancer progression and tumorigenesis. In this review, we summarize the contributions of N6-methyladenosine modification to cancer biology and pathogenesis in the context of both RNA and DNA. We also highlight the clinical relevance of targeting these modifications as a therapeutic strategy for cancer.

Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling.

Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs. SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy.See related commentary by Affronti and Wellen, p. 1161.This article is highlighted in the In This Issue feature, p. 1143.

Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia.

Cirmtuzumab is a humanized monoclonal antibody (mAb) that targets ROR1, an oncoembryonic orphan receptor for Wnt5a found on cancer stem cells (CSCs). Aberrant expression of ROR1 is seen in many malignancies and has been linked to Rho-GTPase activation and cancer stem cell self-renewal. For patients with chronic lymphocytic leukemia (CLL), self-renewing, neoplastic B cells express ROR1 in 95% of cases. High-level leukemia cell expression of ROR1 is associated with an unfavorable prognosis. We conducted a phase 1 study involving 26 patients with progressive, relapsed, or refractory CLL. Patients received four biweekly infusions, with doses ranging from 0.015 to 20 mg/kg. Cirmtuzumab had a long plasma half-life and did not have dose-limiting toxicity. Inhibition of ROR1 signaling was observed, including decreased activation of RhoA and HS1. Transcriptome analyses showed that therapy inhibited CLL stemness gene expression signatures in vivo. Cirmtuzumab is safe and effective at inhibiting tumor cell ROR1 signaling in patients with CLL.