Maria G. Castro, PhD, is the R.C. Schneider Professor of Neurosurgery, and Professor of Cell and Developmental Biology, at the University of Michigan Medical School. My research program focuses on epigenetic regulation of cancer progression, uncovering the role of oncometabolites in the brain tumor microenvironment (TME), and the development of new therapies for adult and pediatric gliomas, including DIPG. We are investigating the role of the tumor immune-microenvironment in tumor progression and response to therapeutics, crosstalk between cancer cells and hematopoietic stem/progenitor cells, and mechanisms affecting the migration of immune cells from peripheral lymphoid organs to the tumor microenvironment. The study of these basic immunological mechanisms will lead to clinical implementation. The goal of my program is to develop novel treatments for brain tumors based on immunotherapeutics, a new and exciting approach that targets inhibition of tumor growth and recurrence.
Areas of Interest
- Antigen Processing/Presentation
- Cell Homing/Trafficking
- Cytokine Networks
- Innate Immunity
- T-Cell Activation
- Viral Infections in the brain
- Gene Delivery
- Diffuse Intrinsic Pontine Glioma (DIPG)
- Cell Signaling
- Immune Suppression
- T-Cell Biology
- Animal Models of Disease
- Vaccine Development
- Gene Therapy
Pediatric and adult brain cancer biology and therapeutics. Epigenetics, cancer metabolism, and signaling networks that mediate tumor progression. Uncovering the role of secreted cancer ligands in hematopoietic stem cell development and anti-tumor immunity. Nanotechnology to develop novel anti-cancer therapies. DNA damage, DNA damage response, and development of novel combination therapies for both adult and pediatric brain tumors, including novel immunotherapeutic approaches.
Current Research Activity
Mutant IDH1 Glioma Project
Glioma genetic models are needed to uncover mechanisms that mediate tumor progression, the interplay with the tumor microenvironment (TME) and response to therapeutics. We have generated the first genetically engineered mutant IDH1 mouse glioma model and isolated primary neurospheres (NS) from the tumors, which exhibit cancer stem cell-like properties. This has enabled us to develop a transplantable mIDH1 glioma model amenable to testing novel therapies. NS are derived from fully immune-competent (C57BL/6) mice, thus allowing examination of the TME and the impact of tumor mutations on the immune response. Our goals are to assess the effect of mIDH1 on transcription (using mRNA-seq) and on global DNA and histone methylation. The mIDH1 glioma model will also be used to identify promoter/enhancer region-specific changes in histone methylation marks (using chromatin immunoprecipitation followed by deep sequencing, or ChIP-seq). We are collaborating with Dr. Mats Ljungman, who pioneered bromouridine sequencing (Bru-seq), to identify and quantify nascent mRNA and gene transcription rates. Uncovering epigenetic patterning of histone 3 hypermethylation and cytosine modifications using next generation sequencing (NGS) technologies will contribute to the identification of novel pathways and gene regulatory networks which will provide novel insights into disease biology and uncover novel therapeutic targets.
Diffuse intrinsic pontine glioma (DIPG) is a brainstem tumor that affects mainly children and for which there is no effective treatment. The most frequent DIPG mutations affect the N-terminal tail of histone variant H3.3 (encoded by H3F3A) and histone variant H3.1 (encoded by HIST1H3B) and result in the change of a lysine to methionine at residue 27, precluding methylation or acetylation of this key regulatory post-translational modification. In addition, six recurrent somatic activating mutations in ACVR1, which encodes for a bone morphogenetic protein (BMP) type-I receptor, have also been identified in DIPG tumors. BMP has very context-specific roles in the brain during development but its role in pediatric cancer remains unknown. We are using the Sleeping Beauty Transposase System to generate spontaneous in vivo tumor models that will allow us to analyze the contributions of these genes to DIPG pathogenesis. This work will elucidate how ACVR1 and H3K27M mutations contribute to DIPG progression and evaluate their impact on tumor response to DNA damaging agents. These studies will uncover novel therapeutic targets to improve prognosis for patients who suffer from DIPG.
The adult and pediatric brain tumor models we have established in our lab are ideal for developing and testing novel immunotherapies as they are implemented in mice with a fully competent immune system. We are using both immune mediated gene therapy strategies and nanoparticle-based vaccination approaches to develop new treatment strategies for these devastating brain cancers.
Our innovative work has led to an FDA-approved gene therapy Phase 1 clinical trial for malignant brain cancer which is currently enrolling patients at the University of Michigan.
Honors & Awards
- Chair, Program Committee, American Society of Cell and Gene Therapy 15th Annual Meeting, Philadelphia, PA, May 2011 – June 2012.
- Appointed the R. C. Schneider Collegiate Professor of Neurosurgery, University of Michigan Medical School, October 2013.
- Top Female Professional in Neurosurgery and Neuroscience in Worldwide Who’s Who. Life-time designation. Worldwide Branding, Uniondale, New York, USA, effective May 2014.
- Appointed to the President’s Advisory Commission on Women’s Issues, University of Michigan, September 2014.
- Featured in the Women of Color in the Academy Project 50th Anniversary Special Exhibit. Center for the Education of Women, University of Michigan, September 2014.
- Awarded the John R. Ohlfest Memorial Lecture Award for Innovative and Collaborative Excellence in the Field of Neuro-Oncology. The 3rd Minnesota Neuro-Oncology Symposium, Minneapolis, Minnesota, May 9, 2016.
- Invited Member of the European Academy for Tumor Immunology (EATI), June 2016.
- Member, Advisory Committee, Physical Sciences in Oncology Center (PSOC), University of Minnesota, 2017 – 2019.
- Chair, Immune Responses to Gene & Cell Therapy Committee, American Society of Gene and Cell Therapy, 2018 – 2020.
- Chair, National Institutes of Health, Clinical Neuroimmunology and Brain Tumors Study Section (CNBT), Center for Scientific Review, July 1, 2018 – June 30, 2020.
- Recipient of the Dean’s Basic Science Research Award, University of Michigan Medical School, November 2018.
- Recipient of the Inaugural Rogel Faculty Scholars Award, 2019 - 2022.
- Elected Fellow, The American Academy for the Advancement of Science, 2019.
- Elected Member, The Latin American Academy of Sciences (ACAL), Caracas, Venezuela, 2020.
- Forbes Scholar Award, Forbes Institute for Cancer Discovery, University of Michigan Medical School, 2020-2022.
- Member, The American Brain Tumor Association (ABTA) Scientific Advisory Council, 2022.
BSc Hons (1st Class) Chemistry, School of Biological Sciences, National University of La Plata, Argentina, 1979
M.Sc. - Biochemistry, School of Biological Sciences, National University of La Plata, 1981
M.Sc. - Education Technology, School of Biological Sciences, National University of La Plata, 1986
Ph.D. - Biochemistry, School of Biological Sciences, National University of La Plata, 1986
Institute for Endocrine Studies, School of Medicine, National University of Argentina at La Plata, 1983
Institute for Endocrine Studies, School of Medicine, National University of Argentina at La Plata, 1986
Fogarty International Visiting Research Fellow, Laboratory of Neurochemistry and Neuro-immunology, National Institute of Child Health and Human Development, National Institutes of Health, 1988
Laboratory of Molecular Endocrinology, Department of Biochemistry and Physiology, University of Reading, United Kingdom, 1990
A complete list of Dr. Castro's grant support is located here.
A complete list of Dr. Castro's recent publications is located here.