Positions

Selected Publications

Academic Article

Year Title Altmetric
2019 IL-11 induces encephalitogenic Th17 cells in multiple sclerosis and experimental autoimmune encephalomyelitis 2019
2019 Recent Developments and Future Directions in Adult Lower-Grade Gliomas: Society for Neuro-Oncology (SNO) and European Association of Neuro-Oncology (EANO) Consensus. 2019
2018 Cross-species transcriptional analysis reveals conserved and host-specific neoplastic processes in mammalian glioma 2018
2018 A Revised Diagnostic Classification of Canine Glioma: Towards Validation of the Canine Glioma Patient as a Naturally Occurring Preclinical Model for Human Glioma. 2018
2018 LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases 2018
2018 Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma. 2018
2018 Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling. 2018
2018 Sustained Delivery of Doxorubicin via Acetalated Dextran Scaffold Prevents Glioblastoma Recurrence after Surgical Resection 2018
2018 Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02. 2018
2018 Frequency of breast cancer subtypes among African American women in the AMBER consortium 2018
2018 Intra-cavity stem cell therapy inhibits tumor progression in a novel murine model of medulloblastoma surgical resection. 2018
2018 MerTK as a therapeutic target in glioblastoma 2018
2018 PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition. 2018
2018 Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model 2018
2017 Putting "multiforme" back into glioblastoma: Intratumoral transcriptome heterogeneity is a consequence of its complex morphology 2017
2017 Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma 2017
2017 Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer 2017
2017 Pharmacokinetics and efficacy of doxorubicin-loaded plant virus nanoparticles in preclinical models of cancer 2017
2017 Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma 2017
2017 Ki-67 Expression in Breast Cancer Tissue Microarrays 2017
2017 Pineal region glioblastoma, a case report and literature review 2017
2017 The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation 2017
2017 Tumor-homing cytotoxic human induced neural stem cells for cancer therapy 2017
2017 Intrinsic Astrocyte Heterogeneity Influences Tumor Growth in Glioma Mouse Models 2017
2017 Paired Expression Analysis of Tumor Cell Surface Antigens. 2017
2016 Hematopoietic Stem cell transplantation and lentiviral vector-based gene therapy for Krabbe's disease: Present convictions and future prospects 2016
2016 BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea–Induced Gliomagenesis 2016
2016 Creation of an NCI comparative brain tumor consortium: Informing the translation of new knowledge from canine to human brain tumor patients 2016
2016 Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide 2016
2016 Performance of three-biomarker immunohistochemistry for intrinsic breast cancer subtyping in the AMBER consortium 2016
2016 Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma 2016
2016 Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma 2016
2015 Erratum: Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation (Oncogene (2015) 34 (3881) DOI:10.1038/onc.2015.204) 2015
2015 Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas 2015
2015 IL2 inducible T-cell kinase, a novel therapeutic target in Melanoma 2015
2015 Efficacy of carboplatin alone and in combination with ABT888 in intracranial murine models of BRCA-mutated and BRCA-wild-type triple-negative breast cancer 2015
2015 ASC deficiency suppresses proliferation and prevents medulloblastoma incidence. 2015
2015 Contemporary murine models in preclinical astrocytoma drug development 2015
2015 Ras-mediated modulation of pyruvate dehydrogenase activity regulates mitochondrial reserve capacity and contributes to glioblastoma tumorigenesis 2015
2014 Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models 2014
2014 Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process 2014
2014 Modeling astrocytoma pathogenesis In vitro and In vivo using cortical astrocytes or neural stem cells from conditional, genetically engineered mice 2014
2014 Development of DNA Damage Response Signaling Biomarkers using Automated, Quantitative Image Analysis 2014
2014 Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal 2014
2014 ClearCode34: A prognostic risk predictor for localized clear cell renal cell carcinoma 2014
2014 Where are we now? and where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) Low-grade Glioma Research Workshop 2014
2014 αb-crystallin: A novel regulator of breast cancer metastasis to the Brain 2014
2013 The Role of Ect2 Nuclear RhoGEF Activity in Ovarian Cancer Cell Transformation 2013
2013 Evolutionary etiology of high-grade astrocytomas 2013
2013 The somatic genomic landscape of glioblastoma 2013
2013 Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis 2013
2013 Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class 2013
2013 Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system 2013
2013 Prediction of lung cancer histological types by RT-qPCR gene expression in FFPE specimens 2013
2013 Cerebellar granule neuron progenitors are the source of Hk2 in the postnatal cerebellum. 2013
2013 Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation 2013
2013 HIF1α and HIF2α independently activate SRC to promote melanoma metastases 2013
2013 MERTK receptor tyrosine kinase is a therapeutic target in melanoma 2013
2013 Pharmacokinetics and Efficacy of PEGylated Liposomal Doxorubicin in an Intracranial Model of Breast Cancer 2013
2013 Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer 2013
2013 Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. 2013
2013 Glioblastoma multiforme: Relationship to subventricular zone and recurrence 2013
2013 Validation of interobserver agreement in lung cancer assessment: Hematoxylin-eosin diagnostic reproducibility for non-small cell lung cancer: The 2004 world health organization classification and therapeutically relevant subsets 2013
2012 Diagnostic utility of major basic protein, eotaxin-3, and leukotriene enzyme staining in eosinophilic esophagitis 2012
2012 LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma 2012
2012 Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation 2012
2012 Genetically engineered mouse models of diffuse gliomas 2012
2012 An Animal Model of MYC-Driven Medulloblastoma 2012
2012 Markers of tyrosine kinase activity in eosinophilic esophagitis: A pilot study of the FIP1L1-PDGFRα fusion gene, pERK 1/2, and pSTAT5 2012
2011 Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases 2011
2011 High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma 2011
2011 The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases 2011
2011 Gene expression profiling of gliomas: Merging genomic and histopathological classification for personalised therapy 2011
2011 Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease 2011
2011 Gone FISHing: Clinical lessons learned in brain tumor molecular diagnostics over the last decade 2011
2011 RhoGDI2 antagonizes ovarian carcinoma growth, invasion and metastasis 2011
2010 Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types 2010
2010 Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1 2010
2009 Malignant gliomas with primitive neuroectodermal tumor-like components: A clinicopathologic and genetic study of 53 cases 2009
2009 Risk of recurrence of resected stage i non-small cell lung cancer in elderly patients as compared with younger patients 2009
2008 Copy-number analysis of topoisomerase and thymidylate synthase genes in frozen and FFPE DNAs of colorectal cancers 2008
2008 Gray zones in brain tumor classification: Evolving concepts 2008
2008 A clinical model to estimate recurrence risk in resected stage I non-small cell lung cancer 2008
2007 Transglutaminase 2 inhibitor, KCC009, disrupts fibronectin assembly in the extracellular matrix and sensitizes orthotopic glioblastomas to chemotherapy 2007
2007 PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer 2007
2007 Glioblastoma: Morphologic and molecular genetic diversity 2007
2007 Multifocal Langerhans cell histiocytosis of the pediatric spine: A case report and literature review 2007
2007 Pharmacogenomics of cancer chemotheraphy-induced toxicity 2007
2006 Significance of necrosis in grading of oligodendroglial neoplasms: A clinicopathologic and genetic study of newly diagnosed high-grade gliomas 2006
2005 Δ24-hyCD adenovirus suppresses glioma growth in vivo by combining oncolysis and chemosensitization 2005
2002 Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: Implications for a dual modality treatment using capecitabine and irradiation 2002
2002 Application of molecular biology studies to gene therapy treatment strategies 2002
2002 Quantitation of cytosine deaminase mRNA by real-time reverse transcription polymerase chain reaction: A sensitive method for assessing 5-fluorocytosine toxicity in Vitro 2002
2002 Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas 2002
2000 Selectivity of tag-72-targeted adenovirus gene transfer to primary ovarian carcinoma cells versus autologous mesothelial cells in vitro 2000
1999 A system for the propagation of adenoviral vectors with genetically modified receptor specificities 1999
1999 Retargeting to EGFR enhances adenovirus infection efficiency of squamous cell carcinoma 1999
1998 Differential susceptibility of primary and established human glioma cells to adenovirus infection: Targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer 1998
1998 An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor- independent cell entry mechanism 1998
1998 Targeting adenoviral infection with basic fibroblast growth factor enhances gene delivery to vascular endothelial and smooth muscle cells 1998
1998 Characterization of an adenovirus vector containing a heterologous peptide epitope in the HI loop of the fiber knob 1998
1997 Development of monoclonal antibodies to the malondialdehyde- deoxyguanosine adduct, pyrimidopurinone 1997
1996 Towards the use of replicative adenoviral vectors for cancer gene therapy. 1996
1996 Efficient delivery of triplex forming oligonucleotides to tumor cells by adenovirus-polylysine complexes 1996

Chapter

Year Title Altmetric
2014 In Situ Hybridization.  699-704. 2014
2009 Cancer gene therapy.  589-612. 2009

Research Overview

  • My laboratory research focuses on diffuse gliomas, a diverse group of primary brain tumors. The most malignant of these, glioblastoma (GBM), is currently diagnosed by microscopic morphology and treated empirically with concurrent fractionated external beam radiation (XRT) and the DNA alkylating agent temozolomide (TMZ) to yield a median overall survival of 12-14 months. Neither diagnosis nor therapy are based upon the underlying molecular alterations responsible for gliomagenesis, the roles of which are becoming increasingly defined using genetically-engineered mouse (GEM) models. The main goal of our work is to establish a direct link between preclinical drug development in glioma GEM and the rational design of human clinical trials involving patients with molecular subtypes of tumor via comparative molecular analyses. To facilitate this work, we have established collaborations with several UNC and non-UNC investigators, including Gary Johnson and Fernando Pardo-Manuel de Villena at UNC, as well as Mike Berens and Jason Huse at TGen and MD Anderson.

    GEM are valuable resources for investigation of the genetic basis of neoplasia. However, these models are not ideal for preclinical drug development. We have developed a series of GEM orthotopic allograft model of gliomas that not only recapitulates the growth pattern of human tumors in vivo but also represents a genetically-tractable model system for drug development. Because clinical trials involve patients with recurrent tumors that have failed standard treatments, identification of molecular correlates of therapy resistance in glioma GEMM will facilitate preclinical drug development with these models and inform future molecular marker-based clinical trial design. We hypothesize that therapy-induced molecular changes in allograft GEM models are similar to recurrent human GBM. To investigate this hypothesis, we are harvesting tumors terminally and systematically during experimental therapies and analyzing them for genomic and proteomic (kinome profiling) techniques to define therapy-specific molecular effects. Genomics data from untreated allografts will be compared with those from its conditional, inducible counterpart to validate the biological fidelity of this model system. Therapy-induced changes in allografts will be compared to those in recurrent human GBM to identify potential markers of therapy resistance.

    The relationship between neuroglial ontogeny and gliomagenesis remains unclear. We have shown that GFAP+ astrocytes are susceptible to genetically-induced gliomagenesis in over ten inducible GEM models using CreER and conditional oncogenic alleles to mutate the core intracellular signaling pathways altered in human gliomas: the G1/S cell cycle, receptor tyrosine kinase/mitogen-activated protein kinase/phosphatidylinositol-3-kinase (RTK/MAPK/PI3K) pathways. Three of these models develop low-grade astrocytomas that rapidly progress to large, lethal GBM, suggesting that secondary genetic events develop stochastically. Similar GEM models of GBM targeting Nestin+ neural stem cells (NSC) have recently been described. However, comparative GEM modeling and genomic studies targeting different brain cells with identical genetic lesions are lacking. We hypothesize that cell-of-origin dictates human subtype-specificity of GBM in GEM. To address this question, we are currently examining the genotype-specific effects on tumor signatures of GEM GBM. We utilize genomics techniques to identify secondary mutations that occur during tumor development and to define their effects on molecular tumor subtypes at the mRNA, DNA, epigenetic, and kinome levels. Finally, although conditional, inducible GEMM are designed based on the molecular abnormalities present in human GBM, the extent to which they recapitulate human GBM molecular biology has yet to be established. Therefore, we are performing comparative genomics between mouse and human GBM to define the effects of cell-of-origin and genetics on human GBM subtypes. Such data will permit future drug/biomarker development studies for specific subtypes of human GBM.

    Precision medicine promises to revolutionize oncology by tailoring treatments to specific somatic mutations within a patient’s tumor. Yet this approach fails to account for the effect of host genetics (germline variations) on tumor evolution and treatment response. It also fails to account for possible genetic interactions between host and tumor. GBM is a genomically diverse disease with fatal outcomes and few effective treatments. Despite the fact that GBM was the first tumor to be characterized by The Cancer Genome Atlas (TCGA), and several genome-wide association studies have linked specific polymorphisms to disease susceptibility, little is known about the impact of host genetics on its biology or treatment response. We have established collaborations with Fernando Pardo-Manuel de Villena (UNC) and Mike Berens (TGen) with expertise in population genetics of inbred and outbred mouse strains, specifically the Collaborative Cross (CC), and human GBM biology and preclinical models, respectively, to complement our experience with GEM models of GBM, to address whether germline variations contribute to differences in GBM evolution or response to therapy.

    We are doing so using a unique experimental approach that utilizes non-germline GEM (nGEM) models. Germline GEM tumors are driven by predefined mutation(s) in specific cell types in their native environment. GEM are essential tools for functional validation of GBM genes, such as NF1 and TP53, but their use has been limited by variable tumor penetrance/latency and lack of cell culture counterparts. To overcome these limitations, the Miller lab developed nGEM models that target specific mutations to predefined brain cells implicated in the origin of GBM, including Nf1;Trp53 deletion mutations in oligodendrocyte progenitor cells (OPC). Transplanting cultured nGEM cells into the brains of syngeneic mice mimics the human disease. Using this nGEM model in the context of the CC will permit us to experimentally define host genes that influence GBM evolution and treatment response. We will use this system to test the hypothesis that genetic polymorphisms affecting expression of ligand-receptor(s) that mediate paracrine effects within the tumor microenvironment impact GBM evolution and response to therapy.

    Precision medicine also fails to account for the dynamic state of tumor kinomes – the repertoire of expressed kinases. Indeed, researchers still view kinome circuits as static and remain focused on the small subset of kinases that are mutated in cancer. “Driver mutations” in kinases such as BRAF (melanoma), ERBB2 (breast cancer), and BCR-ABL (leukemia) have justified this narrow focus, but the problem is that many potentially important kinases for drug discovery remain understudied. This continues, in part, because of a lack of understanding of the entire kinome and appropriate methods to study its dynamics. Our collaborator, Gary Johnson (UNC), developed a novel, unbiased proteomics technique - multiplex inhibitor beads-mass spectrometry (MIB-MS) - to examine dynamic, drug-induced changes in the activation state of the kinome en masse. This includes “understudied kinases” that lack selective inhibitors, antibody reagents, characterized networks & cellular functions, and defined disease relevance. Thus, a major question in cancer biology remains which understudied kinases in the kinome “dark matter” are critical signaling nodes where targeted drug modulation would elicit clinical responses.
    Through our collaborations with Mike Berens (TGen) and Jason Huse (MD Anderson), we have combined our expertise in glioma GEM models to incorporate patient-derived xenograft (PDX) models into our experimental armamentarium. PDX accurately recapitulate the genomic heterogeneity and pathological features of GBM and thus represent the most biologically faithful models of human GBM to date. Through the Ivy Clinical Trial Consortium, Dr. Berens developed and genetically characterized PDX from a “basket” Feasibility Trial where recurrent GBM patients are prospectively recommended targeted therapies based on genome profiling. These PDX harbor 2 groups of mutations:
    Group 1: Validated mutations in the G1/S checkpoint (CDKN2A) and RTK/MAPK/PI3K (EGFR, NF1, PTEN) core GBM pathways.
    Group 2: More recently described mutations in ATRX and IDH1, in combination with TP53.
    Whereas PDX are limited by requirement for immunodeficient hosts, GEM model tumors are driven by predefined mutation(s) in specific cell types in their native environment. GEM are essential for functional validation of GBM target genes, but their use in preclinical drug development has been limited by variable penetrance/latency and lack of cell culture counterparts. Moreover, the typical gene-centric modelling approach has largely ignored the impact of cellular origin on disease pathogenesis. To overcome these limitations, we developed non-germline GEM (nGEM) models that target specific mutations to predefined cells implicated in the origin of GBM subtypes, including neural stem cells (NSC), astrocytes (AC), and oligodendrocyte progenitors (OPC). Transplanting these cultured cells into syngeneic hosts mimics the human disease. We are thus developing nGEM models with the same Gr1/Gr2 driver mutations as our PDX models to:
    1. credential PDX models against human GBM by MIB-MS kinome proteomics
    2. develop nGEM models from distinct cells of origin that are genetically-matched to specific PDX
    3. credential PDX and nGEM models by high-throughput drug screening and monitoring of the dynamic transcriptome and kinome response.
    Our work will help realize the promise of precision medicine in neuro-oncology. Combining PDX and nGEM models and credentialing both with comprehensive molecular analyses will help elucidate the role of mutations and cellular origin in gliomas and the response of their mutated or aberrant signaling circuits to unique combinations of targeted kinase inhibitors. Genomically annotated, syngeneic nGEM models will be useful for future preclinical development of drugs targeting the tumor microenvironment and intact immune system.
  • Teaching Overview

  • Trainees in my laboratory gain valuable experience in translational neuro-oncology, mouse models, genetics/genomics, proteomics, developmental neurobiology, molecular biology and pathology. I provide one-on-one mentorship of research personnel and trainees in my own research laboratory as well as the UNC Translational Pathology Laboratory, including undergraduates, graduate students, research staff, staff scientists, research track assistant professors, residents, and fellows. I give lectures and lead small group discussions (laboratories) in several didactic courses in the UNC School of Medicine and Graduate Schools. I lead the second-year medical school curriculum in neuropathology and lecture in multiple classes offered by the Graduate Program in Pathobiology and Translational Science. I have also served on many graduate student thesis committees and Preliminary examination committees. I am on the admissions committee of the Medical Scientist Training Program (MSTP, MD-PhD) and Biological and Biomedical Sciences Program (BBSP, PhD) and the leadership team of the Graduate Program in Translational Medicine. My overall teaching philosophy is based upon the belief that each individual student is ultimately responsible for his/her own education. I therefore encourage trainees, as well as technical staff, to develop a personalized program of continuous, self-directed learning tailored to their own specific interests and I provide them with organization, focus, and direction to achieve their personal goals. I maintain an “open-door” policy to foster candid discussion and camaraderie and ensure that trainees have guidance so that they may refine their individualized learning approach over time.
  • Education And Training

  • Washngton University School of Medicine, Barnes-Jewish & St. Louis Children's Hospital Pathology, Residency 2004
  • Washington University School of Medicine, Barnes-Jewish & St. Louis Children's Hospitals Pathology, Postdoctoral Fellowship 2006
  • Washington University School of Medicine Division of Molecular Oncology, Department of Medicine, Postdoctoral Fellowship 2006
  • Washington University School of Medicine Division of Neuropathology, Department of Pathology and Immunology, Postdoctoral Fellowship 2005
  • University of Alabama at Birmingham Divisions of Radiation Biology and Neurosurgery,, Postdoctoral Fellowship 2002
  • University of Alabama at Birmingham UAB Gene Therapy Center, Postdoctoral Fellowship 1999
  • Full Name

  • C. Ryan Miller