Update Your ProfileAcademic Title:
Associate Professor
Primary Appointment:
Otorhinolaryngology-Head & Neck Surgery
Location:
Health Sciences Facility III, 670 West Baltimore St, Baltimore 21201
Phone (Primary):
410 706 2609
Fax:
410 706 0729
Education and Training
- B.Sc. in Molecular Biology, Moscow State University, Moscow, Russia, 2004
- M.Sc. in Molecular Biology (Magna Cum Laude), Moscow State University, Moscow, Russia, 2005
- Ph.D. in Cellular and Molecular Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, 2009
Biosketch
As a cancer biologist with a background in pharmacology, the ultimate goal of Dr. Gaykalova is to develop novel cancer therapies, particularly for tumor types that lack effective disease-specific treatment options, such as head and neck squamous cell carcinoma (HNSCC). She heads the translational laboratory, which defines the functional role of epigenetics in the regulation of expression of canonical and alternatively spliced transcripts. Her team has recently characterized the landscape of the cancer-specific alternative splicing events (ASE) in HNSCC and defined their potential role in cancer formation. Moreover, her data suggest that chromatin, and in particular, enhancers, have a regulatory role in the expression of cancer-specific ASE isoforms. The further analysis will help to investigate the interplay between open chromatin and ASE isoform expression, define the role of ASE on cancer formation, and help to determine the detailed functional role of enhancers on the expression of ASE isoforms, which significantly contribute to HNSCC formation. Her work also suggests that both of these processes (alternative isoform expression and chromatin remodeling) can be therapeutically controlled. Such potential therapeutic strategies can form the basis for the development of effective disease-specific therapeutics for this disease and other solid tumors.
Dr. Gaykalova is an expert in the wide variety of biochemical and molecular biology techniques from PCR to in vitro assembly of transcription machinery complexes, as well as cancer and cell biology techniques from gene cloning and transfection to CRISPR and drug treatment of different in vivo and in vitro models, as well as further functional evaluation (cell proliferation, migration, and invasion) of the treated cells. Her group is specialized in the high-throughput analysis of gene expression landscape and chromatin structure in different models and tissue types on both bulk and single-cell level. Dr. Gaykalova has multiple papers documented her expertise bridging the divide between the diversity of such experimental data, high throughput data integration, and robust experimental validation. These and other wet-lab experiences were gained over many years of wet-lab training, practicing, teaching, and leading.
Main scientific discoveries
- Discovered the detailed mechanism of PolII transcription through chromatin
- Defined the role of the first transcribed nucleosome in PolII transcription regulation
- Assigned the role of BORIS transcription factor in HNSCC regulation through epigenetic modulation
- Described the landscape of alternative splicing in HPV- and HPV+ HNSCC
- Defined the role of chromatin in HNSCC development and HPV integration
- Described the role of the NOTCH pathway in HNSCC development
- Discovered primary DNA methylation markers of HNSCC
Research/Clinical Keywords
Mouth squamous cell carcinoma, head and neck cancer, HPV, genomics, cancer epigenetics, chromatin, gene expression, transcription regulation, alternative splicing, epigenetic therapeutics, immune regulation in cancer, immune regulation of tumor development, data integration, genome-wide analysis
Highlighted Publications
Kelley DZ, Flam EL, Izumchenko E, Danilova LV, Wulf HA, Guo T, Singman DA, Bahman A, Skaist A, Considine M, Stavrovskaya E, Bishop JA, Westra WH, Khan Z, Koch WM, Sidransky D, Wheelan S, Favorov AV, Califano JA, Fertig EJ, Gaykalova DA. Integrated analysis of whole-genome ChIP-Seq and RNA-Sequencing data of primary tumor samples associates HPV integration sites with open chromatin marks. Cancer Res. 2017 Sep 25. PMCID: PMC6029614
Guo T, Sakai A, Afsari B, Considine M, Danilova L, Favorov AV, Kelley DZ, Flam EL, Khan Z, Wheelan S, Gutkind S, Fertig EJ*, Gaykalova DA*, Califano JA*. Definition of Alternative Splice Expression in HPV-related oropharyngeal cancer includes a novel functional splice variant of AKT3. Cancer Res. 2017 Oct 1;77(19):5248-5258. doi: 10.1158/0008-5472.CAN-16-3106. Epub 2017 July 21st. PMID: 28733453. *Equal contribution
Kelley DZ, Flam EL, Guo T, Danilova LV, Zamuner F, Bohrson C, Considine M, Windsor EJ, Bishop JA, Zhang C, Koch WM, Sidransky D, Westra WH, Chung CH, Califano JA, Wheelan S, Favorov AV, Florea L, Fertig EJ, Gaykalova DA. Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma. Transl Res. 2018 Jul 26. pii: S1931-5244(18)30108-7. doi: 10.1016/j.trsl.2018.07.007. [Epub ahead of print]. PMCID: PMC6218276
Flam EL, Danilova L, Kelley DZ, Stavrovskaya E, Guo T, Considine M, Qian J, Califano JA, Favorov A, Fertig EJ, Gaykalova DA. Differentially Methylated Super-Enhancers Regulate Target Gene Expression in Human Cancer. Sci Rep. 2019 Oct 21;9(1):15034. doi: 10.1038/s41598-019-51018-x. PMID: 31636280.
Guo T, Zambo KDA, Zamuner FT, Ou T, Hopkins C, Kelley DZ, Wulf HA, Winkler E, Erbe R, Danilova L, Considine M, Sidransky D, Favorov A, Florea L, Fertig EJ, Gaykalova DA. Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma. Epigenetics. 2020 Mar 22:1-13. doi: 10.1080/15592294.2020.1741757. PMID: 32164487
Kagohara LT, Zamuner F, Davis-Marcisak EF, Sharma G, Considine M, Allen J, Yegnasubramanian S, Gaykalova DA*, Fertig EJ*. Integrated single-cell and bulk gene expression and ATAC-seq reveals heterogeneity and early changes in pathways associated with resistance to cetuximab in HNSCC-sensitive cell lines. Br J Cancer. 2020 May 4. doi: 10.1038/s41416-020-0851-5. Online ahead of print.PMID: 32362655. *Equal contribution
Lopatina T, Favaro E, Danilova L, Fertig EJ, Favorov AV, Kagohara LT, Martone T, Bussolati B, Romagnoli R, Albera R, Pecorari G, Brizzi MF, Camussi G, Gaykalova DA. Extracellular Vesicles Released by Tumor Endothelial Cells Spread Immunosuppressive and Transforming Signals Through Various Recipient Cells. Front Cell Dev Biol. 2020 Sep 9;8:698. doi: 10.3389/fcell.2020.00698. eCollection 2020.PMID: 33015029
Additional Publication Citations
Complete List of Published Work in My Bibliography:
https://www.ncbi.nlm.nih.gov/myncbi/daria.gaykalova.1/bibliography/public/
Research Interests
The epigenetic landscape of head and neck cancer tissues: In order to demonstrate that head and neck cancer is an epigenetically driven disease, the Gaykalova lab performed chromatin- and DNA methylation-based treatment of HNSCC and salivary adenoid cystic carcinoma samples using JQ1, an inhibitor of the BET family of bromodomain proteins that recognize acetylated lysine residues, as well as azacitidine, an inhibitor of DNA methyltransferases. Strong cellular responses to both of these drugs were observed, supporting the primary hypothesis. To define the functional role of epigenetics in head and neck cancer formation, the team described the whole-genome landscape of chromatin structure and DNA methylation for head and neck samples. They also characterized the role of chromatin and DNA methylation on regulating gene expression of the most potent oncogenes and tumor suppressors and their associated pathways. The newly developed protocol for the whole-genome chromatin analysis of small surgical samples was described in their recent Cancer Research paper. This work showed that the chromatin landscape plays a central role in cancer-specific gene expression profiles and viral genome integration. These scientific directions of the group are summarized in the review “Epigenetic Regulation of Gene Expression in Cancer: Techniques, Resources, and Analysis.”
Tumor type-specific gene expression profiles of head and neck cancer: Epigenetic and genetic abnormalities regulate disease-specific gene expression changes, which lead to the dysregulation of oncogene and tumor suppressor pathways. To adequately define gene expression profiles, the group performed whole-genome RNA-Seq and array-based analyses of HNSCC tissues. The team determined their tissue type-specific oncogenes and tumor suppressors and their regulating transcription factors. Importantly, this work helped to identify the tumor type-specific alternative splicing profiles of both HPV+ and HPV- HNSCC. Tumor-specific alternatively spliced proteins can potentially be adopted as therapeutic targets, anti-cancer vaccine development targets, or disease biomarkers due to their unique tissue specificity. This research, featured in Cancer Research, Epigenetics, Translational Research, and other papers, defined the role of genetic and epigenetic changes in aberrant gene expression, including alternative splicing events and gene fusions. The group has also participated in the development of new computational methodologies for improved detection of gene expression changes.
The role of transcription factors in head and neck cancer development: In addition to high-throughput head and neck cancer analysis and pathway discovery, the Gaykalova lab is focused on analyzing individual transcription factors, such as STAT1, STAT3, NF-κB, BORIS, TFIIS, FACT, and others. They demonstrated that individual genes are recognized by transcription factors that cause DNA methylation changes, the histone mark landscape, and nucleosome positioning near their transcription start sites to regulate gene expression. Moreover, recent literature suggests that the location of epigenetic enhancer regions and the composition of their associated transcription factors are very tissue-specific. Therefore, knowing the tumor type-specific location of enhancers, it is possible to predict the master transcription factors that regulate tumor type-specific expression. They recently discovered tissue-specific enhancers and their associated transcription factors using modern detection tools.
The therapeutic venues for HNSCC: There is no effective treatment for HNSCC, as the response rate for the targeted and immune treatment is low, and the recurrence rate is high. The goal of the Gaykalova lab is to fill this scientific knowledge gap and the clinical need. Overall, the team identified multiple therapeutic targets, enabling the further study of their inhibitors. Thus, the epigenetic treatment could be successfully combined with targeted therapeutics to enhance treatment response and to decrease resistance to single-agent therapies. The lab continues efforts on defining the role of chromatin in canonical and alternative gene expression and the role of epigenetic and targeted therapies in the regulation of HNSCC progression.
Awards and Affiliations
- Diploma of Honors Degree (Magna Cum Laude), Moscow State University, 2005
- Conference Travel Award, UMDNJ, 2006, 2008
- Young Investigator Award, UMDNJ, 2006, 2007, 2008, 2009
- Financial Aid Award, Genetics Society of America, 2008
- Best Publication by a Graduate Student, UMDNJ, 2009
- American Head and Neck Society Pilot Grant Award, AHNS, 2012
- Head and Neck Cancer Specialized Program of Research Excellence (HNC-SPORE) Pilot Grant Award, NIH, 2014, 2015
- Head and Neck Cancer Specialized Program of Research Excellence (HNC-SPORE) Career Enhancement Program Core, NIH, 2015
- R21 Exploratory/Developmental Research Grant Award, NIH/NIDCR, 2015
- Cervical Cancer Specialized Program of Research Excellence (HNC-SPORE) Career Development Program, NIH, 2017
- Catalyst Award, Johns Hopkins University, 2018
- NIH Research Project Grant (Parent R01) “Defining the chromatin structure signature that drives pre-malignant transformation”, NIH/NIDCR, 2019
- American Cancer Society, Research Scholar, 2021
Grants and Contracts
Active:
05/01/19-04/30/24 NIH R01DE027809 “Delineating Chromatin-Related Gene Expression Signatures as a Function of HNSCC Progression”
09/16/14 – 06/30/20 ECOG 30006561 “CCT 4085-20-EA3161-ECOG-ACRIN-NCI Coop Ga”
Pending:
07/01/21-06/30/25 ACS RSG533967 “Defining the functional role of enhancer-regulation of transcription factors in HPV+ HNSCC” Awarded
Completed:
08/01/18 – 07/31/19 NIH 5P50DE019032 Pilot Project “The discovery of alternative splicing in HPV-related head and neck squamous cell carcinoma”
09/01/17 – 08/31/18 NIH 5P50CA098252 Carrier Development Program “The role of chromatin in tumorigenesis of cervical cancers”
04/01/13-03/31/18 NIH/NCI R01DE023347 Subsite P.I. “Epigenetic Biomarker Discovery in HPV related HNSCC”
07/01/15-06/30/17 NIH/NIDCR R21DE025398 “Characterizing genome-wide alternative splicing in HPV related HNSCC”
08/01/15 – 07/31/17 NIH 5P50DE019032 Pilot Project “The discovery of differentially methylated super-enhancer elements in HPV-related OPSCC”
08/01/14 – 07/31/15 NIH 5P50DE019032 Pilot Project “The discovery of alternative splicing in HPV-related head and neck squamous cell carcinoma”
07/31/12-06/31/13 American Head and Neck Society 241446 “Transcription Factor Signature of Head and Neck Squamous Cell Carcinoma”
Professional Activity
National/International Service
Journal editor activities
2020-present Current Research in Microbial Sciences
Journal peer reviewer activities
2013-present PloS One Journal
2014-present Head and Neck Journal
2015-present International Journal of Cancer
2016-present Oral Oncology
2016-present Scientific Reports
2017-present Clinical Epigenetics
2017-present Cancer Letters
2019-present Pharmacology & Therapeutics
2019-present Bioinformatics
2021-present Nature Communications
Grant reviewer at study sections
2015 The Voelcker Fund Grant
2016 Oral, Dental and Craniofacial Sciences Study Section, NIH, R01/R21
2018 Million Veteran Program
2018 DSR, NIDCR Special Grants Review Committee, NIH, F31/K01/R03
2019 Medical Research Council, U.K.
2020 NIDCR Special Emphasis Panel ZDE1 Study Section, NIH, R03
2021 NIDCR R03 Secondary Data Analysis Study Section, NIH, R03
Organizational activities
2017, 2019 The Co-chair of the Future of Biomedicine Young Scientist Forum, FEFU, Russia
2018-present The Course Director of “BioTech 39: Epigenetics”, FAES, NIH, Bethesda, MD
2019 The Chair of Molecular Medicine Session, FOB International Conference, FEFU, Russia
Advisory committees
2008-2009 The North Jersey Regional Science Fair, Judge
2015-2019 Toby Eagle Foundation, Award Committee member
Local Service
Grant reviewer
2018 The STAR Grant for Undergraduate Research, Johns Hopkins University
2019 The Catalyst Grant, Johns Hopkins University
2019 The Discovery Grant, Johns Hopkins University
Links of Interest
Previous Positions
- Research Assistant, Department of Molecular biology, School of Biology, Moscow State University, Moscow, 2003 - 2004
- Research Assistant, Department of Pharmacology, UMDNJ - Robert Wood Johnson Medical School, Piscataway, NJ, 2004 - 2005
- Ph.D. Student, Department of Pharmacology, UMDNJ - Robert Wood Johnson Medical School, Piscataway, NJ, 2005 - 2009
- Postdoctoral Fellow, Johns Hopkins University, Baltimore, MD, 2009 - 2014
- Instructor, Johns Hopkins University, Baltimore, MD, 2014 - 2016
- Assistant Professor, Johns Hopkins University, Baltimore, MD, 2016 - 2020