Publications by authors named "Sameer Agnihotri"

Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate.

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Article Synopsis
  • H3K27M diffuse midline gliomas (DMG) consist of two main types of cells: less-differentiated oligodendrocyte precursor-like stem cells and more differentiated astrocyte-like cells.
  • Researchers created models representing these cell types and used various profiling techniques to understand their distinct metabolic programs, identifying specific weaknesses in each type.
  • The study found that astrocyte-like cells are more prone to a type of cell death called ferroptosis, while oligodendrocyte precursor-like cells are sensitive to statins and inhibitors of mitochondrial function, suggesting targeted therapies could improve treatment outcomes for patients with these tumors.
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Background: Glioblastoma (GBM) is an aggressive cancer with limited treatment options. Immunotherapy targeting CD69, an early activation marker on T cells, has shown promise in preclinical models of non-CNS malignancies. This study investigates anti-CD69 therapy alone or in combination with anti-PD-1 in a preclinical GBM model.

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MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) . Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling.

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  • Radiotherapy is the main treatment for a deadly type of brain cancer in kids called diffuse midline glioma (DMG), which has a special genetic mutation (H3K27M).
  • Researchers found that this mutation makes the tumors weaker against radiation when combined with a medicine called PARP inhibitor (like olaparib), which can help fight the cancer.
  • The study showed that using PARP inhibitors with radiotherapy also boosts the immune system, allowing it to attack the cancer cells better, which could be an important new treatment for kids with DMG.
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Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.

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  • Diffuse hemispheric gliomas, specifically H3G34R/V-mutant, are aggressive brain tumors with no current targeted therapies and come from neural precursor cells.
  • Researchers found that these tumors display developmental patterns similar to healthy brain interneurons and identified key genes that these tumor cells depend on, especially CDK6.
  • Targeting CDK6 with inhibitors showed promising results in reducing tumor growth and improving survival in experimental models, with one patient showing a significant response to treatment.
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Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues.

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Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes.

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Article Synopsis
  • Scientists found that a type of brain cancer called glioblastoma has special cells that make more proteins than usual.
  • They discovered that a tiny machine called YRDC helps these cancer cells change their building blocks (tRNA) to make proteins faster.
  • Reducing threonine in food made these cancer cells grow slower and worked better with some cancer treatments, suggesting diet might help fight cancer.
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  • Metabolic changes in pediatric diffuse midline glioma are influenced by the H3K27M histone mutation, which activates oncogenic pathways.
  • The RAS pathway and ERK5 kinase are crucial for tumor growth in these gliomas, with ERK5 playing a key role in cell proliferation and glycolysis.
  • Targeting the ERK5-PFKFB3 signaling axis with multi-targeted drugs could be an effective treatment strategy for patients with this type of cancer.
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Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial.

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Low-grade epilepsy-associated tumors (LEATs) are a common cause of drug-resistant epilepsy in children. Herein, we demonstrate the feasibility of using tumor tissue derived from stereoelectroencephalography (sEEG) electrodes upon removal to molecularly characterize tumors and aid in diagnosis. An 18-year-old male with focal epilepsy and MRI suggestive of a dysembryoplastic neuroepithelial tumor (DNET) in the left posterior temporal lobe underwent implantation of seven peri-tumoral sEEG electrodes for peri-operative language mapping and demarcation of the peri-tumoral ictal zone prior to DNET resection.

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Temozolomide (TMZ) is a standard treatment for glioblastoma (GBM) patients. However, TMZ has moderate therapeutic effects due to chemoresistance of GBM cells through less clarified mechanisms. Here, we demonstrate that TMZ-derived 5-aminoimidazole-4-carboxamide (AICA) is converted to AICA ribosyl-5-phosphate (AICAR) in GBM cells.

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Purpose: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state.

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While the majority of meningiomas encountered clinically are sporadic, there is a rare subset that arises due to early life or childhood irradiation. Sources of this radiation exposure may be due to treatment of other cancers such as acute childhood leukemia, other central nervous system tumors such as medulloblastoma, the treatment of tinea capitis (rarely and historically), or environmental exposures, as seen in some of the Hiroshima and Nagasaki atomic bomb survivors. Regardless of their etiology, however, radiation-induced meningiomas (RIMs) tend to be highly biologically aggressive irrespective of WHO grade and are usually refractory to the conventional treatment modalities of surgery and/or radiotherapy.

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Unlabelled: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation.

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Diffuse midline glioma (DMG) is a pediatric cancer that originates in the midline structures of the brain. Prognosis of DMG patients remains poor due to the infiltrative nature of these tumors and the protection they receive from systemically delivered therapeutics via an intact blood-brain barrier (BBB), making treatment difficult. While the cell of origin remains disputed, it is believed to reside in the ventral pons.

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In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance.

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Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas.

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Background: Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptors.

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How abnormal neurodevelopment relates to the tumour aggressiveness of medulloblastoma (MB), the most common type of embryonal tumour, remains elusive. Here we uncover a neurodevelopmental epigenomic programme that is hijacked to induce MB metastatic dissemination. Unsupervised analyses of integrated publicly available datasets with our newly generated data reveal that SMARCD3 (also known as BAF60C) regulates Disabled 1 (DAB1)-mediated Reelin signalling in Purkinje cell migration and MB metastasis by orchestrating cis-regulatory elements at the DAB1 locus.

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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).

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Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation.

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