About

514
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Introduction
Maria G Castro currently works at the Department of Neurosurgery and the Department of Cell and Developmental Biology, University of Michigan. Maria does research in Neurooncology, malignant gliomas, glioblastoma multiforme DIPG, Clinical Immunology, Cancer Research and Neuroscience. One of the current projects in the lab. involves uncovering the role of the 'CXCR4/CXCL12 signaling pathway in Glioma.' Another current project is uncovering the role of mutant IDH1 in the reprogramming of the tumor transcriptome in models of mouse low grade gliomas and also in human mutant IDH1 low grade gliomas. Our lab is also working on the development of o novel mouse model for diffuse intrinsic pontine glioma (DIPG) and its use in the testing and implementation of novel immunotherapy strategies.
Research Experience
August 2011 - November 2018
University of Michigan
Position
  • Professor (Full)
January 2011 - December 2012
University of Michigan School of Medicine
Position
  • Professor (Full)
January 2007 - present
University of Minnesota Twin Cities
Position

Publications

Publications (514)
Article
Full-text available
Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially g...
Article
Full-text available
Glioblastoma (GBM) metabolism has traditionally been characterized by a primary dependence on aerobic glycolysis, prompting the use of the ketogenic diet (KD) as a potential therapy. In this study we evaluated the effectiveness of the KD in GBM and assessed the role of fatty acid oxidation (FAO) in promoting GBM propagation. In vitro assays reveale...
Preprint
Mutation in isocitrate dehydrogenase (mIDH) is a gain of function mutation resulting in the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits DNA and histone demethylases. The resultant hypermethylation phenotype reprograms the glioma cells transcriptome and elicits profound effects on glioma immunity. We report that in mouse mo...
Article
Full-text available
Malignant gliomas are the most common and aggressive primary brain tumor in adults, and high mitotic rates are associated with their malignancy. Gliomas were modeled in mice using the Sleeping Beauty system to encode genetic lesions recapitulating the human disease. The presented workflow allows the study of the proliferation of glioma cells in viv...
Article
Purpose: Gliomas are brain tumors with dismal prognoses. The standard-of-care treatments for gliomas include surgical resection, radiation, and temozolomide administration; however, they have been ineffective in providing significant increases in median survival. Antigen-specific cancer vaccines and immune checkpoint blockade may provide promising...
Article
Full-text available
Introduction: Gliomas are infiltrating brain tumors associated with high morbidity and mortality. Current standard of care includes radiation, chemotherapy and surgical resection. Today, survival rates for malignant glioma patients remain dismal and unchanged for decades. The glioma microenvironment is highly immunosuppressive and consequently this...
Preprint
Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas subtype ha...
Article
Glioma is one of the most common primary malignant tumors of the central nervous system (CNS), accounting for approximately 40% of all intracranial tumors. Temozolomide (TMZ) is a conventional chemotherapy drug for adjuvant treatment of patients with high-risk gliomas, including grade II to grade IV. Our bioinformatic analysis of TCGA and CGGA data...
Article
Purpose: Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, ACVR1-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. Experimental design: We utilized the Sleeping Beauty transposase system to generate an endogenous mou...
Preprint
Full-text available
Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance, and new strategies that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we found that purine metabolites stro...
Article
Full-text available
Background Gliomas are the most common primary brain tumors. High Grade Gliomas have a median survival of 18 months, while Low Grade Gliomas (LGG) have a median survival (MS) of ~7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH) enzyme. Survival of these patients ranges from 1-15 years, and tumor mu...
Article
Full-text available
Colon carcinomas comprise over two-thirds of all colorectal cancers with an overall 5-year survival rate of 64%, which rapidly decreases to 14% when the cancer becomes metastatic. Depending on the stage of colon carcinoma at diagnosis, patients can undergo surgery to attempt complete tumor resection or move directly to chemotherapy with one or a co...
Article
Diffuse intrinsic pontine glioma (DIPG) is a rare but deadly pediatric brainstem tumor. To date, there is no effective therapy for DIPG. Transcriptomic analyses have revealed DIPGs have a distinct profile from other pediatric high-grade gliomas occurring in the cerebral hemispheres. These unique genomic characteristics coupled with the younger medi...
Preprint
Full-text available
Gliomas are the most common primary brain tumors. High Grade Gliomas have a median survival of 18 months, while Low Grade Gliomas (LGG) have a median survival of ~7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH1) enzyme (IDH1R132H). Survival of these patients ranges from 1-15 years, and tumor mutat...
Article
Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU ( MAPT ), a gene that has...
Article
Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of...
Article
Background: High grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas....
Article
Diffuse Gliomas represent 80% of brain tumors with an average survival of the most aggressive form glioblastoma (GBM) 15-22 months from the time of diagnosis. The current standard of care includes tumor resection, chemotherapy and radiation, nevertheless, the incidence of recurrence remains high and there is a critical need for developing new thera...
Preprint
Full-text available
Glioblastoma multiforme (GBM), the predominant and most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in parts, due to the absence of effective drug delivery strategies. Intravenous injection is the simplest and least invasive delivery route to the brain, but has been severely limited by the ina...
Preprint
Purpose: Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, ACVR1-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy. Experimental Design: We utilized the Sleeping Beauty transposase system to generate an endogenous mouse...
Article
Gliomas are the most common primary brain tumors; patients exhibit a poor prognosis. Mutations in isocitrate dehydrogenase (mIDH) are present in most patients with lower grade glioma (LGG), and are correlated with better prognosis and survival. We postulated that mIDH1 induces epigenetic reprogramming leading to alteration in immune cells’ function...
Article
Patients with mutant IDH1 gliomas survive ~3.8 year longer than patients harboring wildtype IDH1 glioma, irrespective of histology or genetic lesions, making mutant IDH1 an essential prognostic indicator. Mutant IDH1 gliomas are highly infiltrative with a high incidence of relapse. We are studying a low grade glioma subtype, genetically characteriz...
Article
Mesenchymal gliomas are the most aggressive tumors that carry the worst prognosis. The origins of mesenchymal cells within brain tumors, remains poorly understood. They could originate either from invading mesenchymal cells, from perivascular smooth muscle actin+ cells, or from a mesenchymal transformation of tumor cells. Identifying the origin and...
Article
Gliomas are a leading cause of cancer mortality in children and adults and new targeted therapies are desperately needed. ATRX is a chromatin remodeling protein that is recurrently mutated in H3F3A-mutant pediatric GBM and IDH-mutant grade 2/3 adult glioma. We previously showed that loss of ATRX in glioma results in tumor growth and additional tumo...
Article
This is an interim report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. Lack of dendritic cells from the brain precludes anti-glioma immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recrui...
Article
Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) attributes to poor efficacy of chemotherapy and/or immunotherapy. We recently reported that SLC9A1 gene expression (Na/H exchanger 1, NHE1) in GBM tumor correlates with increased macrophage tumor infiltration and worsened patient survival. Temozolomide (TMZ) monotherapy, the stand...
Article
Gliomas are the most frequently diagnosed human primary brain tumors. Mutations in Isocitrate Dehydrogenase (IDH) 1 occur in the vast majority of low grade gliomas and secondary high grade glioblastomas. A single amino acid missense mutation in IDH1 at arginine 132 (R132H) is an early event in tumor development. IDH1R132H leads to the production of...
Article
Mutated Isocitrate dehydrogenase 1 (IDH1R132H; mIDH1) is found in 50% of all adult gliomas and in 80% of lower-grade gliomas. IDH1R132H promotes 2-hydroxyglutarate production which inhibits histone and DNA demethylases, inducing epigenetic reprogramming of the tumor transcriptome. We recently demonstrated that epigenetic reprogramming enhances DNA-...
Article
Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins are key regulators of tissue and lineage-specific gene differentiation during embryogenesis. Previous work has shown that H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes,...
Article
There is currently much excitement for the use of immunotherapies in cancer. In spite of positive results using checkpoint inhibitors in melanoma and CAR T cells in leukemias, these strategies have not yet achieved robust clinical responses in human gliomas. A powerful inhibitory microenvironment is thought to be the culprit. Mechanisms that determ...
Article
Pediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months and are the most common malignant brain tumors in children. No significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study these tumors is critical. Recurrent mutations in genes encoding histones H3.3...
Article
INTRODUCTION An inadequate immune response is increasingly recognized as a central element in the pathogenesis of high-grade glioma. Based on our prior work, we hypothesized that dendritic cell dysfunction plays a key role in poor anti-brain tumor immunity. To stimulate a robust immune response against high-grade glioma, we developed a strategy to...
Article
Full-text available
Research into the immunological processes implicated in cancer has yielded a basis for the range of immunotherapies that are now considered the fourth pillar of cancer treatment (alongside surgery, radiotherapy and chemotherapy). For some aggressive cancers, such as advanced non-small-cell lung carcinoma, combination immunotherapies have resulted i...
Conference Paper
Pediatric high-grade glioma (pHGG) accounts for 8-12% of central nervous system tumors and has a 90% mortality rate. Consequently, novel therapies are needed to advance treatment options and improve survival rates. A means to do this is through designing a mouse model that accurately mirrors pHGG in humans to further study this type of pHGG and des...
Conference Paper
Pediatric high-grade glioma (pHGG) accounts for 8-12% of central nervous system tumors and has a 90% mortality rate. Consequently, novel therapies are needed to advance treatment options and improve survival rates. A means to do this is through designing a mouse model that accurately mirrors pHGG in humans to further study this type of pHGG and des...
Conference Paper
A molecular subtype of low grade gliomas (LGG) is characterized by mutations in Alpha-Thalassemia Mental Retardation X-linked (ATRX), TP53 and isocitrate dehydrogenase 1 (IDH1R132H, mIDH1). Our lab has generated a genetically engineered mouse model that harbors the characteristic genetic lesions found in this molecular subtype of LGG. We determined...
Article
2019 Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. The absence of functional dendritic cells from the brain precludes anti-brain tumor immune responses. We combined t...
Article
Oligodendroglioma is an indolent, chemosensitive glioma characterized by 1p/19q co-deletion. This loss of genetic information may be responsible for its unique treatment sensitivity. Our preliminary data suggests a role for the 1p gene, isoprenylcysteine carboxylmethyltransferase (ICMT). ICMT is the only enzyme to methylate prenylcysteine subtrates...
Article
Pediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months, are the most common malignant brain tumors in children and no significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study this tumor is critical. Recurrent mutations in genes encoding histones H3.3 a...
Article
Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brainstem tumor that originates in the pons. Mutations in Activin-A Receptor Type 1 (ACVR1), a bone morphogenetic protein (BMP) receptor, are highly recurrent and specific for DIPG. The ACVR1 mutations co-occur with the H3.1 K27M mutation. The K27M mutations are found in 80% of DIPG pati...
Article
ATRX is a histone chaperone protein recurrently mutated in pediatric GBM. We previously confirmed its role in tumor progression and mutational burden in glioma. However, the mechanism which mediates the proliferative advantage of ATRX loss in pediatric GBM remains unexplained. Recent data revealed a distinct pattern of DNA binding sites of the ATRX...
Article
We recently demonstrated that Cav1 (caveolin-1) is a negative regulator of Stat3 (signal transducer and activator of transcription-3) activity in mouse fibroblasts and human lung carcinoma SHP77 cells. We now examined whether the cellular context may affect their levels as well as the relationship between them, by assessing Cav1 and Stat3-ptyr705 a...
Preprint
In vivo genetic knockdown of the proto-oncogene Fyn in immunocompetent mouse glioma models significantly extended survival by 25%-77%. GSEA analysis of DE genes revealed a highly significant enrichment of gene ontologies related to immune function such as STAT-1 regulated cell differentiation, IFNγ signaling, T cell activation, and NK cytotoxicity....
Article
Full-text available
Brain metastases are the most lethal complication of advanced cancer; therefore, it is critical to identify when a tumor has the potential to metastasize to the brain. There are currently no interventions that shed light on the potential of primary tumors to metastasize to the brain. We constructed and tested a platform to quantitatively profile th...
Article
Full-text available
OBJECTIVES/SPECIFIC AIMS: Oncostreams represent a novel growth pattern of GBM. In this study we uncovered the cellular and molecular mechanism that regulates the oncostreams function in GBM growth and invasion. METHODS/STUDY POPULATION: We studied oncostreams organization and function using genetically engineered mouse gliomas models (GEMM), mouse...
Article
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1 R132H ) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53 ) gene, and loss-of-function mutations in alpha thalassemia/mental r...
Preprint
Full-text available
Classification of gliomas as wild-type or mutant IDH1/2 tumors has profound clinical implications. However, how these two groups of gliomas progress, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau is epigenetically induced by mutant IDH1/2, whereas is almost absent from tumors with E...
Article
Full-text available
Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, for which there is no cure. Treatment effectiveness for GBM has been limited due to tumor heterogeneity, an immunosuppressive tumor microenvironment (TME) and the presence of the blood brain barrier, which hampers the transport of chemotherapeutic compounds to the central nervous s...
Article
Analysis of protein expression in glioma is relevant for several aspects in the study of its pathology. Numerous proteins have been described as biomarkers with applications in diagnosis, prognosis, classification, state of tumor progression, and cell differentiation state. These analyses of biomarkers are also useful to characterize tumor neurosph...
Chapter
Gliomas are the most common malignant brain tumors in the pediatric population. Even though great efforts have been made to understand their distinctive molecular characteristics, there has not been any improvements in the median survival in decades. In children, high-grade glial tumors have a median survival of 9-15 months. It has recently been de...
Chapter
Despite advances in uncovering the molecular mechanisms that mediate glioma progression and the implementation of novel therapeutic modalities, patients' prognosis remains dismal. This is due to both systemic and local tumor induced immune suppression. We are particularly interested in the role played by infiltrating immunosuppressive myeloid deriv...
Article
Full-text available
Mutant IDH1 gliomas have are heterogeneous tumors with a high incidence of relapse. We are studying a glioma subtype, genetically characterized by inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, TP53 and gain of function mutations in isocitrate dehyrdogenase 1 (mIDH1). Mutation in IDH1 converts α-ketoglutra...
Article
Glioblastomas (GBM) are the most frequent and aggressive primary tumors of the brain. Fyn, a Src family kinase member, is overexpressed in human GBM. Its function, however, remains poorly understood. We analyzed the differential gene expression (DE) of highly malignant tumor (NPA: N-Ras/shp53/shATRx) compared to a less malignant one (NPAI: N-Ras/sh...
Article
Molecular characterization studies have illustrated that mutation in isocitrate dehydrogenase (mIDH1) enzyme, which is present in most patients with low grade glioma (LGG) and secondary glioma is correlated with better prognosis and survival [1]. We hypothesize that mIDH1 impacts tumor immunity by altering the phenotype and function of tumor infilt...
Article
High-grade glioma (HGG) is the most common and lethal type of primary brain tumor in humans, remaining essentially incurable; 16% of pediatric and young adult HGGs in cerebral hemispheres encode Gly34Arg/Val (G34R/V) substitutions in the histone variant H3.3. It was shown that H3.3G34R/V leads to a local downregulation of H3K36 trimethylation at sp...
Article
Full-text available
GBM remains the deadliest primary malignant brain tumor. Given the importance of invading cells, less attention has been paid to the tumor mass, even if such a mass eventually kills the patient. We previously demonstrated that human and mouse transplantable or GEMM gliomas display regular anatomical multicellular structures containing elongated cel...
Article
Diffuse intrinsic pontine glioma (DIPG) is pediatric brain tumor that occurs in the pons and for which there is no treatment. Mutations in Activin-A Receptor Type 1 (ACVR1), a bone morphogenetic protein (BMP) receptor, are highly recurrent and specific for DIPG. We used the Sleeping Beauty Transposase (SB) system to deliver plasmids encoding NRASV1...
Article
Full-text available
IDH1-R132H is the most common mutation in lower-grade glioma and secondary glioblastoma. It is expressed in combination with ATRX and p53 inactivation in a mIDH1 glioma subtype which has been associated with better prognosis. We hypothesized that this is mediated by the impact of epigenetic changes on DNA-repair and DNA damage response (DDR) which...
Article
Full-text available
The weak immunogenicity of gliomas presents a barrier for effective immunotherapy. Na/H exchanger isoform 1 (NHE1) maintains alkaline intracellular pH (pHi) of glioma cells and acidic microenvironment. In addition, NHE1 is expressed in tumor-associated microglia and tumor-associated macrophages (TAMs) and involved in protumoral communications betwe...
Preprint
Full-text available
Glioma patients whose tumors carry a mutation in the Isocitrate Dehydrogenase 1 (IDH1R132H) gene are younger at the time of diagnosis and survive longer. The molecular glioma subtype which we modelled, harbors IDH1R132H, tumor protein 53 (TP53) and alpha thalassemia/mental retardation syndrome X-linked (ATRX) loss. The impact of IDH1R132H on genomi...
Article
Tumors in the brain-stem are difficult to diagnose and treat primarily owing to the location. Diffuse intrinsic pontine glioma (DIPG) is a fatal paediatric brain-stem tumor located in the ventral pons with 100% fatality. These tumors are often treated on the assumption that DIPGs are molecularly similar to adult high grade gliomas; however, they ar...
Conference Paper
Metastasis from the primary tumor site to the brain is the most lethal complication of advanced breast cancer. There is no translational approach to detect if a primary tumor has brain metastatic potential. This is due to a lack of blood brain barrier (BBB) models that can classify a cells metastatic potential. Moreover, the mechanisms by which cir...
Article
ID1 regulates transcription by interacting with bHLH transcription factors and previous work has shown that over-expression of the recurrent DIPG H3F3A K27M and ACVR1 mutations in cultured astrocytes lead to an increase in ID1 expression; this has not been validated in human DIPG. DNA (exome)/RNA sequencing of 34 DIPGs and 17 normal samples (SickKi...
Article
Full-text available
Introduction: ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered: We discuss...
Article
Full-text available
Background: Glioblastoma (GBM) is an aggressive and highly vascular tumor with median survival below 2 years. Despite advances in surgery, radiotherapy and chemotherapy survival has improved modestly. To combat glioma vascular proliferation anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) were introduced. Preclinically th...
Article
Full-text available
There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic inter...
Article
Epigenetic modifications may be involved in the development and progression of glioma. Changes in methylation and acetylation of promoters and regulatory regions of oncogenes and tumor suppressors can lead to changes in gene expression and play an important role in the pathogenesis of brain tumors. Native chromatin immunoprecipitation (ChIP) is a p...