Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently completed his nearly two-year role as Editor of a volume, “Melanoma: Methods and Protocols,” that was published this week in the prestigious Methods in Molecular Biology book series. This series, published by Springer Nature/Humana Press, has been the leading series in biomedical protocol publishing since its inception 35 years ago. The volume includes contributions from authors at major research universities and cancer research centers across the world and features protocols ranging from basic research techniques to clinical and veterinary medicine procedures used in the study, diagnosis, and treatment of melanoma.
Among the 45 book chapters in the volume are two chapters authored by Dr. Hargadon that are based on techniques developed/optimized in his research lab at H-SC. The first chapter, entitled “A Flow Cytometric Assay for Investigating Melanoma Cell Adhesion to Lymphatic Endothelial Cells,” is based on a technique developed to study melanoma cell interactions with lymphatic endothelial cells, a process critical to melanoma invasion of regional lymph nodes. This chapter includes former Hampden-Sydney student, Coleman Johnson ’19, as a co-author. The second chapter, entitled “Generation of Functional Gene Knockout Melanoma Cell Lines by CRISPR-Cas9 Gene Editing,” describes an optimized protocol for engineering melanoma cells using gene editing technology and highlights the approach employed by Dr. Hargadon to knock out the Foxc2 gene in a murine melanoma cell line, work that is featured in recent publications by Dr. Hargadon in the journals Cancer Genomics and Proteomics and Frontiers in Oncology. This book chapter also includes 3 Hampden-Sydney student co-authors (Coleman Johnson, Corey Williams ’19, and David Bushhouse ’19) who contributed to this work. Of note, Coleman Johnson and Corey Williams are currently in their second year as medical students at Virginia Commonwealth University’s School of Medicine, and David Bushhouse, a former Goldwater Scholar at the College, is in his second year as a Ph.D. candidate in Northwestern University’s Interdisciplinary Biological Sciences Graduate Program.
The “Melanoma: Methods and Protocols” volume is available at:
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 was recently named one of 19 finalists for the Molecular Cloud Distinguished Research Awards for Genome Editing. Among the 19 finalists, Dr. Hargadon is the only investigator to lead a team comprised entirely of undergraduate students. His research group received the Most Social Impact Team Award for its genome editing work in melanoma. Specifically, Dr. Hargadon and his team employed CRISPR-Cas9 gene editing technology to engineer a novel mouse melanoma cell line with a disrupted FOXC2 gene and used this model to demonstrate a role for the FOXC2 transcription factor in melanoma progression. This work has resulted in multiple publications with H-SC student co-authors in the journals Cancer Genomics and Proteomics, Frontiers in Oncology, and Cancer Genetics, as well as a book chapter on CRISPR-Cas9 gene editing in “Melanoma – Methods and Protocols,” a recently published volume edited by Dr. Hargadon for the prestigious Methods in Molecular Biology book series.
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published an article in the journal Cancer Genetics highlighting the prognostic significance of FOXC2 gene expression in tumor biopsies. Using publicly available data from clinical specimens catalogued in The Cancer Genome Atlas, a landmark cancer genomics program that molecularly characterized more than 20,000 tissue specimens across 33 different cancer types, Dr. Hargadon identified FOXC2 RNA levels in tumor biopsies as a novel biomarker predictive of patient survival and response to several widely used chemotherapeutics. This work, conducted in collaboration with Hampden-Sydney student and co-author Eli Strong ’20, represents the most comprehensive evaluation of FOXC2 as an RNA-level biomarker for cancer to date, and it is the first to identify the prognostic value of FOXC2 gene expression as a determinant of patient response to chemotherapy. This study highlights the potential of using FOXC2 gene expression in tumor biopsy samples as a biomarker to guide appropriate treatment regimens most likely to yield clinical benefit in cancer patients.
Eli Strong, who contributed to the data analysis for this work, was Valedictorian of the Class of 2020 and is currently in his first year of medical school at George Washington University. He is also co-author on another article published with Dr. Hargadon in the journal Cancer Genomics and Proteomics (2019), which describes work conducted in a novel, genetically engineered mouse melanoma model that was used to identify a role for the FOXC2 transcription factor in melanoma progression.
The most recent article in Cancer Genetics can be found here:
Downloadable PDF available at: https://authors.elsevier.com/a/1cdoT7sh1pLAGy
Collaborative Bioinformatics Research with H-SC Student Taylor J. McGee ’23 Highlights New Biomarkers of Melanoma Patient Response to Immunotherapy
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published an article entitled “Genomic and Transcriptional Changes in IFNg Pathway Genes are Putative Biomarkers of Response to Ipilimumab Immunotherapy in Melanoma Patients” in the journal Expert Review of Clinical Immunology. This invited article is a Key Paper Evaluation highlighting a seminal paper in the field of tumor immunology from the laboratory of Nobel Laureate Dr. James Allison, who developed the first FDA-approved immunotherapeutic for a cancer treatment strategy known as immune checkpoint blockade. Since the approval of ipilimumab in 2011, ipilimumab’s success as a therapeutic has spearheaded the development of several other now-approved immune checkpoint inhibitors, all of which function by “unleashing” anti-tumor immune responses that are otherwise restrained in cancer patients. Though the success of these therapies has led to unprecedented clinical outcomes for many cancer patients, there remain others who either fail to respond to therapy or exhibit disease recurrence after a short response. The work from Dr. Allison’s group highlighted in Dr. Hargadon’s Key Paper Evaluation was the first to describe defects in genes associated with the IFNg pathway as a mechanism of tumor escape from ipilimumab-associated immune responses. Specifically, mutations and other alterations to genes that control this pathway in tumor cells were found to drive tumor resistance to therapy-induced immune responses.
As part of his evaluation of this seminal work, through the College’s Faculty Fellowship Program this past summer Dr. Hargadon conducted additional bioinformatics research with Hampden-Sydney student, Taylor J. McGee ’23, to assess whether non-genomic alterations to the IFNg pathway also correlated with patient response to ipilimumab. Using clinical data from melanoma patients catalogued in The Cancer Genome Atlas, Dr. Hargadon and Taylor found that RNA levels for several IFNg pathway genes also correlate with patient response to ipilimumab. These new data indicate that not only are direct changes to IFNg pathway genes associated with tumor resistance to therapy, but so too are alterations in IFNg pathway gene expression levels. These findings further highlight the significance of the IFNg pathway as a determinant of anti-tumor immune efficacy as first described by Dr. Allison’s group at MD Anderson Cancer Center, and they reveal the potential utility of RNA-level biomarkers associated with this pathway that could be used to predict patient response to immunotherapy in the future.
Taylor McGee, a co-author on this article, is a sophomore at Hampden-Sydney College and plans to pursue his Ph.D. in computational biology following his graduation in 2023. His ultimate career goal is to apply novel computational models to the study of problems in the field of HIV research.
The article authored by Dr. Hargadon and Taylor can be found at: https://www.tandfonline.com/doi/full/10.1080/1744666X.2021.1847644?scroll=top&needAccess=true
Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published a major review article entitled “Tumor Microenvironmental Influences on Dendritic Cell and T Cell Function: A Focus on Clinically Relevant Immunologic and Metabolic Checkpoints” in the journal Clinical and Translational Medicine. An invited review commissioned by the journal’s Editor-in-Chief Dr. Xiangdong Wang, Distinguished Professor of Medicine and Director of the Shanghai Institute of Clinical Bioinformatics at the prestigious Fudan University in China, Dr. Hargadon’s article highlights recent advances in immunotherapy and targeted therapy as cutting-edge treatments for cancer. His review discusses in particular the role of key checkpoints that inherently limit the immune and metabolic functions of dendritic cells and T cells within the tumor microenvironment, and it emphasizes how insights into these suppressive pathways have led to the identification of novel targets for therapies designed to enhance the anti-tumor immune functions of these important cell populations. Dr. Hargadon’s article also discusses the potential for combinatorial therapies that target these diverse checkpoints to enhance patient outcome by increasing the percentage of patients likely to benefit from immunotherapy and by overcoming tumor cell resistance to immunotherapy in patients who normally do respond but then ultimately relapse.
Published by John Wiley and Sons (Wiley), Clinical and Translational Medicine is an international, peer-reviewed, and open access journal with aims at 1) promoting and accelerating the translation of preclinical research to a clinical application and 2) enhancing communication between basic and clinical scientists. Dr. Hargadon’s article can be accessed at: https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.37