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  • The phenotypes of proliferating glioblastoma cells reside on a single axis of variation. Cancer discovery Wang, L., Babikir, H., Muller, S., Yagnik, G., Shamardani, K., Catalan, F., Kohanbash, G., Alvarado, B., Di Lullo, E., Kriegstein, A., Shah, S., Wadhwa, H., Chang, S. M., Philips, J. J., Aghi, M. K., Diaz, A. A. 2019

    Abstract

    Although tumor-propagating cells can be derived from glioblastomas (GBMs) of the proneural and mesenchymal subtypes, a glioma stem-like cell (GSC) of the classical subtype has not been identified. It is unclear if mesenchymal GSCs (mGSCs) and/or proneural GSCs (pGSCs) alone are sufficient to generate the heterogeneity observed in GBM. We performed single-cell/nuclei RNA-sequencing of 28 gliomas, and single-cell ATAC-sequencing for 8 cases. We find that GBM GSCs reside on a single axis of variation, ranging from proneural to mesenchymal. In silico lineage tracing using both transcriptomics and genetics supports mGSCs as the progenitors of pGSCs. Dual inhibition of pGSC-enriched and mGSC-enriched growth and survival pathways provides a more complete treatment than combinations targeting one GSC phenotype alone. This study sheds light on a long-standing debate regarding lineage relationships among GSCs and presents a paradigm by which personalized combination therapies can be derived from single-cell RNA signatures, to overcome intra-tumor heterogeneity.

    View details for DOI 10.1158/2159-8290.CD-19-0329

    View details for PubMedID 31554641

  • Insurance type impacts the economic burden and survival of patients with newly diagnosed glioblastoma. Journal of neurosurgery Chandra, A., Young, J. S., Dalle Ore, C., Dayani, F., Lau, D., Wadhwa, H., Rick, J. W., Nguyen, A. T., McDermott, M. W., Berger, M. S., Aghi, M. K. 2019: 1?11

    Abstract

    Glioblastoma (GBM) carries a high economic burden for patients and caregivers, much of which is associated with initial surgery. The authors investigated the impact of insurance status on the inpatient hospital costs of surgery for patients with GBM.The authors conducted a retrospective review of patients with GBM (2010-2015) undergoing their first resection at the University of California, San Francisco, and corresponding inpatient hospital costs.Of 227 patients with GBM (median age 62 years, 37.9% females), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher overall hospital costs for surgery compared to non-Medicaid patients ($50,285 vs $38,779, p = 0.01). Medicaid patients had higher intensive care unit (ICU; p < 0.01), operating room (p < 0.03), imaging (p < 0.001), room and board (p < 0001), and pharmacy (p < 0.02) costs versus non-Medicaid patients. Medicaid patients had significantly longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured patients (3.9 and 1.8 days, p < 0.01). Medicaid patients had similar comorbidity rates to Medicare patients (67.8% vs 68.1%), and both groups had higher comorbidity rates than privately insured patients (37.3%, p < 0.0001). Only 67.7% of Medicaid patients had primary care providers (PCPs) versus 91.5% of Medicare and 86.3% of privately insured patients (p = 0.009) at the time of presentation. Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm, p = 0.03). Preoperative (70 vs 90, p = 0.02) and postoperative (80 vs 90, p = 0.03) Karnofsky Performance Scale (KPS) scores were lowest for Medicaid versus non-Medicaid patients, while in subgroup analysis, postoperative KPS score was lowest for Medicaid patients (80, vs 90 for Medicare and 90 for private insurance; p = 0.03). Medicaid patients had significantly shorter median overall survival (10.7 months vs 12.8 months for Medicare and 15.8 months for private insurance; p = 0.02). Quality-adjusted life year (QALY) scores were 0.66 and 1.05 for Medicaid and non-Medicaid patients, respectively (p = 0.036). The incremental cost per QALY was $29,963 lower for the non-Medicaid cohort.Patients with GBMs and Medicaid have higher surgical costs, longer lengths of stay, poorer survival, and lower QALY scores. This study indicates that these patients lack PCPs, have more comorbidities, and present later in the disease course with larger tumors; these factors may drive the poorer postoperative function and greater consumption of hospital resources that were identified. Given limited resources and rising healthcare costs, factors such as access to PCPs, equitable adjuvant therapy, and early screening/diagnosis of disease need to be improved in order to improve prognosis and reduce hospital costs for patients with GBM.

    View details for DOI 10.3171/2019.3.JNS182629

    View details for PubMedID 31226687

  • Stress Granule Assembly Disrupts Nucleocytoplasmic Transport CELL Zhang, K., Daigle, J., Cunningham, K. M., Coyne, A. N., Ruan, K., Grima, J. C., Bowen, K. E., Wadhwa, H., Yang, P., Rigo, F., Taylor, J., Gitler, A. D., Rothstein, J. D., Lloyd, T. E. 2018; 173 (4): 958-+

    Abstract

    Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.

    View details for PubMedID 29628143

  • Mutant Huntingtin Disrupts the Nuclear Pore Complex NEURON Grima, J. C., Daigle, J., Arbez, N., Cunningham, K. C., Zhang, K., Ochaba, J., Geater, C., Morozko, E., Stocksdale, J., Glatzer, J. C., Pham, J. T., Ahmed, I., Peng, Q., Wadhwa, H., Pletnikova, O., Troncoso, J. C., Duan, W., Snyder, S. H., Ranum, L. W., Thompson, L. M., Lloyd, T. E., Ross, C. A., Rothstein, J. D. 2017; 94 (1): 93-+

    Abstract

    Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin (HTT) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt nucleocytoplasmic transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and nucleocytoplasmic transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT, HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective nucleocytoplasmic transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted nucleocytoplasmic transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this transport defect and neurotoxicity, providing future novel therapy targets.

    View details for DOI 10.1016/j.neuron.2017.03.023

    View details for Web of Science ID 000398262000012

    View details for PubMedID 28384479

    View details for PubMedCentralID PMC5595097

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