SELECTED PUBLICATIONS
Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma
Cell Reports. 2017 Oct 31; 21(5):1399-410.
Glioblastoma (GBM) is the most common primary brain cancer in adults and is notoriously difficult to treat because of its diffuse nature. We performed single-cell RNA sequencing (RNA-seq) on 3,589 cells in a cohort of four patients. We obtained cells from the tumor core as well as surrounding peripheral tissue. Our analysis revealed cellular variation in the tumor's genome and transcriptome. We were also able to identify infiltrating neoplastic cells in regions peripheral to the core lesions. Despite the existence of significant heterogeneity among neoplastic cells, we found that infiltrating GBM cells share a consistent gene signature between patients, suggesting a common mechanism of infiltration. Additionally, in investigating the immunological response to the tumors, we found transcriptionally distinct myeloid cell populations residing in the tumor core and the surrounding peritumoral space. Our data provide a detailed dissection of GBM cell types, revealing an abundance of information about tumor formation and migration.
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http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31462-6
A survey of human brain transcriptome diversity at the single cell level.
PNAS | June 9, 2015 | vol. 112 | no. 23 | 7285–7290
The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level.
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Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse.
Neuron | January 2016 | Volume 89, Issue 1, 6 | Pages 37–53
The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures.
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New tools for studying microglia in the mouse and human CNS.
Proc Natl Acad Sci U S A. 2016 Mar 22;113(12)
Here, we identify transmembrane protein 119 (Tmem119), a cell-surface protein of unknown function, as a highly expressed microglia-specific marker in both mouse and human. We developed monoclonal antibodies to its intracellular and extracellular domains that enable the immunostaining and isolation of microglia. Using our antibodies, we provide, to our knowledge, the first RNAseq profiles of highly pure mouse microglia during development and after an immune challenge.
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Chromosome-scale mega-haplotypes enable digital karyotyping of cancer aneuploidy.
Nucleic Acids Research. 2017 Aug 16.
Genomic instability is a frequently occurring feature of cancer that involves large-scale structural alterations. These somatic changes in chromosome structure include duplication of entire chromosome arms and aneuploidy where chromosomes are duplicated beyond normal diploid content. However, the accurate determination of aneuploidy events in cancer genomes is a challenge. Recent advances in sequencing technology allow the characterization of haplotypes that extend megabases along the human genome using high molecular weight (HMW) DNA. For this study, we employed a library preparation method in which sequence reads have barcodes linked to single HMW DNA molecules. Barcode-linked reads are used to generate extended haplotypes on the order of megabases. We developed a method that leverages haplotypes to identify chromosomal segmental alterations in cancer and uses this information to join haplotypes together, thus extending the range of phased variants. With this approach, we identified mega-haplotypes that encompass entire chromosome arms. We characterized the chromosomal arm changes and aneuploidy events in a manner that offers similar information as a traditional karyotype but with the benefit of DNA sequence resolution. We applied this approach to characterize aneuploidy and chromosomal alterations from a series of primary colorectal cancers.
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Brain tumor mutations detected in cerebral spinal fluid.
Clin Chem. 2015 Mar;61(3):514-22.
Detecting tumor-derived cell-free DNA (cfDNA) in the blood of brain tumor patients is challenging, presumably owing to the blood-brain barrier. Cerebral spinal fluid (CSF) may serve as an alternative "liquid biopsy" of brain tumors by enabling measurement of circulating DNA within CSF to characterize tumor-specific mutations. Many aspects about the characteristics and detectability of tumor mutations in CSF remain undetermined. We detected tumor mutations in CSF samples from 6 of 7 patients with solid brain tumors. The concentration of the tumor mutant alleles varied widely between patients, from <5 to nearly 3000 copies/mL CSF. We identified 7 somatic mutations from the CSF of a patient with leptomeningeal disease by use of cancer panel sequencing, and the result was concordant with genetic testing on the primary tumor biopsy. Tumor mutations were detectable in cfDNA from the CSF of patients with different primary and metastatic brain tumors. We designed 2 strategies to characterize tumor mutations in CSF for potential clinical diagnosis: the targeted detection of known driver mutations to monitor brain metastasis and the global characterization of genomic aberrations to direct personalized cancer care.
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A Novel Brain-Permeant Chemotherapeutic Agent for the Treatment
of Brain Metastasis
in Triple-Negative Breast Cancer
Mol Cancer Ther. 2021 Nov;20(11):2110-2116
Development of metastases to central nervous system (CNS) is an increasing clinical issue following the diagnosis of advanced breast cancer. The propensity to metastasize to CNS varies by breast cancer subtype. Of the four breast cancer subtypes, triple-negative breast cancers (TNBC) have the highest rates of both parenchymal brain metastasis and leptomeningeal metastasis (LM). LM is rapidly fatal due to poor detection and limited therapeutic options. Therapy of TNBC brain metastasis and LM is challenged by multifocal brain metastasis and diffuse spread of LM, and must balance brain penetration, tumor cytotoxicity, and the avoidance of neurotoxicity. Thus, there is an urgent need for novel therapeutic options in TNBCs CNS metastasis. QBS10072S is a novel chemotherapeutic that leverages TNBC-specific defects in DNA repair and LAT1 (L-amino acid transporter type 1)-dependent transport into the brain.
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Comprehensive RNA analysis of CSF reveals a role for CEACAM6 in lung cancer leptomeningeal metastases
NPJ Precis Oncol. 2021 Oct 8;5(1):90
Non-small cell lung cancer (NSCLC) metastatic to the brain leptomeninges is rapidly fatal, cannot be biopsied, and cancer cells in the cerebrospinal fluid (CSF) are few; therefore, available tissue samples to develop effective treatments are severely limited. This study aimed to converge single-cell RNA-seq and cell-free RNA (cfRNA) analyses to both diagnose NSCLC leptomeningeal metastases (LM), and to use gene expression profiles to understand progression mechanisms of NSCLC in the brain leptomeninges.
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Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases.
J Thorac Oncology 2018 Jul;13(7):1022-1027.
When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases.
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Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma
Nature Medicine. 2019 Nov;25(11):1783-1795.
Proinflammatory cytokines in the tumor microenvironment can promote tumor growth, yet their value as therapeutic targets remains underexploited. We validated the functional significance of the cardiotrophin-like cytokine factor 1 (CLCF1)-ciliary neurotrophic factor receptor (CNTFR) signaling axis in lung adenocarcinoma (LUAD) and generated a high-affinity soluble receptor (eCNTFR-Fc) that sequesters CLCF1, thereby inhibiting its oncogenic effects. eCNTFR-Fc inhibits tumor growth in multiple xenograft models and in an autochthonous, highly aggressive genetically engineered mouse model of LUAD, driven by activation of oncogenic Kras and loss of Trp53.
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lAB MEMBERS
Our team combines experience with passion, creativity, and dedication.
Melanie Hayden Gephart
Principal Investigator
Dr. Hayden Gephart did her residency and post doctoral training at Stanford University in neurosurgery and cancer biology. She joined as faculty in 2014 and is a brain tumor neurosurgeon.
Sophia Chernikova
Senior Researcher
Sophia is a cancer biologist with an expertise in DNA repair, epigenetics, genomic instability and radiation oncology. Her present interests are in brain tumors with a specific focus on brain metastases from triple negative breast cancer. She enjoys data mining, hiking and biking.
Shruti Jain
Post Doctorate
Shruti has obtained her PhD in Neuroscience from Kent State University, Ohio in 2017. She has extensive experience in developmental neurobiology and her PhD work was focused on local translation of mRNAs during brain development in Down syndrome. She enjoys traveling, painting and Zumba.
Maxine Umeh
Post Doctorate
Maxine obtained her PhD in Biochemistry, Molecular, Cell and Developmental Biology with an emphasis in Translational Research from UC Davis. She has an extensive background in cancer biology and an interest in triple negative breast cancer, which has a higher incidence and death rate in African-American women. She enjoys volleyball, piano playing, analyzing data, and making pretty graphs.
Adrian John Rodrigues
Medical Student
Adrian is a Stanford medical student interested in neurosurgery. He completed his undergraduate degree in biology and economics at Yale. He enjoys hiking, playing tennis, and reading.
Monica Granucci
Clinical Research Coordinator
Monica Granucci is a Clinical Research Coordinator with the Cancer Clinical Trials Office and the Brain Tumor Center. She works to facilitate research tissue acquisition at Stanford, as well as assisting with the design, conduct, and management of some of Stanford’s Neurosurgery Department’s clinical trials.
Bryanna Godfrey
Undergraduate
Bryanna is an undergraduate at Stanford. She is studying Human Biology with a concentration in neurodegenerative diseases and cancer. She hopes to pursue further studies in medicine or public health. She enjoys reading, cooking, and playing the flute in her free time.
Samuel Wong
Post Doctorate
Sam obtained his PhD in Cellular and Molecular Medicine from Johns Hopkins University, Baltimore in 2020. He has experience in developmental neurobiology and enjoys reading and hiking in his free time.
Crystal Wang
Clinical Fellow
Crystal is a Stanford pediatric hematology/oncology fellow interested in translational oncology research. She went to medical school at Johns Hopkins University School of Medicine and completed her pediatrics residency training at St. Christopher's Hospital for Children in Philadelphia. She enjoys cooking and going to the beach.
Guan Li
Medical Student
Guan is a medical student at Stanford interested in neurosurgery. He completed his undergraduate degree in molecular, cellular, and developmental biology at Yale. He enjoys playing basketball, swimming, and golf during his free time.
Georgiana Burnside
Clinical Research Coordinator Associate
Georgiana is a recent graduate of Stanford University where she studied neurobiology. She is interested in clinical and translational research approaches to spinal cord and brain injury medicine and plans to pursue medical school in the next few years. In her free time, she enjoys watching docuseries, camping, and spending time with family.
Brandon Carlson-Clarke
Clinical Research Coordinator Associate
Brandon is working as a Clinical Research Coordinator with the Cancer Clinical Trials Office and the Brain Tumor Center and will start medical school in the Fall, 2023 with intentions to pursue neurosurgery. He completed his undergraduate degree in neurobiology and behavior at Cornell University. He enjoys skiing, camping, and cooking.
Adriana Noelle Carter
Undergraduate
Adriana is an unergraduate at Stanford studying human biology and creative writing. She plans on attending medical school and is interested in neuroscience and oncology. She is invloved with camp kesem at Stanford, an organization that supports kids whose parent's have cancer, and she is currently training to become an EMT. In her free time, she loves to read and write poetry and fictional stories.
Zachary Jun Xiang Yu
Undergraduate
Zachary is an undergraduate at Stanford. He intends to study both Psychology and Biology, with a focus in cognitive neuroscience and medicine. In his free time, Zach enjoys cooking, playing ultimate frisbee and volleyball.
Saif Ali
Undergraduate
Saif is an undergraduate student majoring in Human Biology with a concentration in brain and behavior. He is extremely interested in neuroscience/neurobiology research and plan on attending medical school shortly after graduation. In his free time, he likes to work out, listen to music, and have recently picked up boxing.
Vaibhavi Bhaviesh Shah
Medical Student
Vaibhavi is a medical student at Stanford interested in neurosurgery. She completed her undergraduate in Biological Engineering and in Science, Technology, and Society at the Massachusetts Institute of Technology (MIT) in 2021. She enjoys playing tennis, running, and listening to music in her free time.
Juliana Nava
Summer Intern
Juliana is a community college student at Cañada College and will transfer to a four-year institution at the end of the following year. She is majoring in general Biology and has an interest in Developmental Biology. In her spare time, she enjoys reading, making art, and playing the guitar.
Thy Trang Hoang Trinh
Life Science Research Professional
Thy is a recent graduate of Denison University with a Bachelor of Science in Biochemistry. She is interested in healthcare and biomedical research, particularly in topics about human physiology and diseases. Thy enjoys cooking, biking, and singing in her free time.
Dan Herrick
Neurosurgery Resident
Dan Herrick is a Stanford Neurosurgery resident and recently completed the Stanford Biodesign Innovation Fellowship. He earned his M.D. and Ph.D. degrees at Tufts University School of Medicine where his Ph.D. research identified novel molecular mechanisms governing adult neurogenesis after injury. He is interested in translational research focused on identifying biomarkers of neurotrauma.
Neuro-oncology research, it's personal
Neurosurgery isn't just my career and practice, it is a personal struggle to help improve the treatment for patients with brain tumors. These diseases have taken the lives of many of my friends and family, and affects the lives of my patients every day. Just a handful of their photos are listed here. We are committed to improving the care of patients with brain tumors and understanding the underlying mechanisms of disease progression, motivated by a personal understanding of the disease. I work in the operating room employing the maximal treatment for patients in my clinic today. The lab looks to develop new treatments and diagnostic techniques for the future patients who will be in the clinic tomorrow.
Robert Bean (1966 - 2000)
Robert Bean, Dr. Hayden's uncle, passed away at the age of 37 from Glioblastoma.
Paul Kalanithi (1977 - 2015)
Paul, Dr. Hayden's co-resident, was diagnosed with metastatic lung cancer during his neurosurgery residency. He passed away at the age of 37.
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