GEPHART LAB
STANFORD NEUROSURGERY
OUR VISION
Our laboratory accelerates translational brain tumor research, combining innovative techniques in genetics and cancer biology with a unique insight into the pressing clinical questions facing patients. We use novel genetic sequencing methods and modeling to understand how cancer grows in the brain, inadvertently supported by native brain cells. We focus on translational therapeutic targets identified from and validated with primary human tissue and cerebrospinal fluid whenever possible, as this most reliably reflects the human disease. These findings have led to novel diagnostic tools and clinical trials for patients with malignant brain tumors. Our laboratory is a dynamic and collaborative working environment, benefitting from the supportive research environment at Stanford. Our laboratory space bridges the Stanford core campus and the medical facilities, emblematic of the translational aspects of our work.
SELECTED PUBLICATIONS
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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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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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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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.
Explore data at:
Read more at:
http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31462-6
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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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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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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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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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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lAB MEMBERS
Our team combines experience with passion, creativity, and dedication.
Melanie Hayden Gephart
Principal Investigator
Sophia Chernikova
Shruti Jain
Post Doctorate
Maxine Umeh
Post Doctorate
Adrian John Rodrigues
Medical Student
Monica Granucci
Clinical Research Coordinator
Bryanna Godfrey
Undergraduate
Samuel Wong
Post Doctorate
Crystal Wang
Clinical Fellow
Georgiana Burnside
Clinical Research Coordinator Associate
Brandon Carlson-Clarke
Clinical Research Coordinator Associate
Adriana Noelle Carter
Undergraduate
Zachary Jun Xiang Yu
Undergraduate
Saif Ali
Undergraduate
Vaibhavi Bhaviesh Shah
Medical Student
Juliana Nava
Summer Intern
Thy Trang Hoang Trinh
Life Science Research Professional
Dan Herrick
Neurosurgery Resident
Leeza Kopaeva
Clinical Research Coordinator Associate
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.
ALUMNI
Wenying Pan
Position in the Lab (2013 - 2016): Graduate Student
Subsequent position Scientist at Grail Inc.
Linya You
Position in the Lab (2015 - 2016): Post doctorate
Subsequent position: Shanghai Medical College of Fudan University
Yingmei Li
Position in the Lab (2014 - 2018): Post doctorate
Subsequent position: Scientist at BindeBio and Chinese Academy of Science.
Ian Connolly
Position in the Lab (2014 - 2019) : Medical Student
Subsequent position: Neurosurgery Resident Physician at Massachusetts General Hospital
Jiaojiao Deng
Position in the Lab (2018 - 2019): Medical Student
Subsequent position: Neurosurgery student at Huashan Hospital, Fudan University.
Eli Johnson
Position in the Lab (2015 - 2020): Medical Student
Subsequent position: Neurosurgery Resident at Duke, University.
Dina Polyak
Position in the Lab (2017 - 2020): Post doctorate
Subsequent position: Scientist at Arsenal Bio.
Lina Khav Khoeur
Position in the Lab (2015 - 2018): Undergraduate
Subsequent position: Medical Student, UCSF
Yuelong Wang
Position in the Lab (2019 - 2020): Visiting Post doctorate
Subsequent position: Assistant Researcher, and Postdoctoral fellow Sichuan University, Chengdu, China
Bina Kakusa
Position in the Lab (2019 - 2021): Medical Student
Subsequent position: Neurosurgery Resident, Stanford
Anna Diaz
Position in the Lab (2021): Summer Intern
Subsequent position: Student at UC Berkeley
Amanda Luu
Position in the Lab (2021): Summer Intern
Subsequent position: Student at UCSD, Majoring in Neuroscience
Hriday P. Bhambhvani
Position in the Lab (2017-2022): Medical Student
Subsequent position: Resident Doctor at Cornell University
Steffi Jean Andersen
Position in the Lab (2018-2022): Undergraduate
Subsequent position: Medical Student, Columbia University
SUPPORT OUR RESEARCH
A gift to the Gephart Lab will support our research on brain tumors.
If you would like to make a donation for this purpose, please click below or contact:
Erik C. Rausch
Medical Center Development
Phone: 650.725.1005
Email: erausch@stanford.edu
Interested in joining our team?
Please submit a CV with a brief description of your research interests and career goals to Melanie Hayden Gephart (mghayden@gmail.com)
We are looking for a postdoctoral scientist to accelerate the study and targeting of malignant brain tumors using genetic tools and primary human samples. A competitive applicant for this position will have an interest in malignant brain tumors, neuroscience, and bioinformatics. Candidates must hold a Ph.D. from an accredited institution in a relevant research field, have strong laboratory, analytical, and organizational skills, and be able to work independently, as well as part of a team. Our work in the laboratory will enhance patient care through an improved understanding of malignant brain tumor biology.
CONTACT US
Melanie Hayden Gephart, MD, MAS
Department of Neurosurgery
213 Quarry Rd
4th Fl MC 5958
Office (650) 723-8591
mghayden@stanford.edu
Clinic
Department of Neurosurgery
875 Blake Wilbur Drive, Clinic D
Palo Alto, California 94304
Clinic (650) 497-7777
Stanford Main Hospital (650) 723 4000
Office
1201 Welch Rd., MSLS P307
Stanford, CA 94305-5487
Office (650) 723-8591
Brain Tumor Center
Clinic Referral/Questions
650-497-7777