Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 was recently named the recipient of an R. Davilene Carter Presidential Prize for Best Manuscript (3rd Prize) for his 2021 publication in the Journal of Cancer Education. His article, entitled “Using The Cancer Genome Atlas as a Tool to Improve Undergraduate Student Understanding of Cancer Genetics and the Hallmarks of Cancer Progression,” highlights a novel bioinformatics approach to educating undergraduate students about genetic influences on cancer progression. Developed by Dr. Hargadon for his Biology 201 – Genetics and Cell Biology course, this approach involves student investigation of clinical cancer datasets publicly available in The Cancer Genome Atlas as a means of gaining insight into various genomic (DNA) and transcriptomic (RNA) aberrations in cancer cells. His paper describes this multi-week, bioinformatics-based project and its impact on improving student understanding of fundamental concepts in genetics and cancer biology. Coupled with an experimental project utilizing murine (mouse) melanoma cell lines, previously highlighted in Dr. Hargadon’s 2016 publication in Biochemistry and Molecular Biology Education, this project is now a major component of Dr. Hargadon’s Experiential Learning section of Biology 201 that is currently being offered as part of the College’s newly implemented Compass Program.

Dr. Hargadon will be recognized as an R. Davilene Carter Presidential Prize recipient at the upcoming International Cancer Education Conference in mid-October. His Journal of Cancer Education article is available at: https://link.springer.com/article/10.1007/s13187-021-01962-y

Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published an article on a central mechanism of melanoma resistance to immunotherapy in the British Journal of Dermatology, one of the most prestigious journals in Dermatology, where it is consistently ranked as the #1 or #2 journal in its field. Dr. Hargadon’s article highlights the diverse mechanisms by which melanoma cells evade type I and type II interferons, proteins released by various immune cell populations that typically exhibit potent anti-tumor activity. Evading the activity of these interferons has emerged as a key correlate of melanoma resistance to various immunotherapies, including immune checkpoint blockade approaches that have become the most attractive treatment options for many cancer patients. Despite the promise of these approaches, however, there remain many cancer patients who either fail to respond to immune checkpoint blockade or who experience disease relapse after a short anti-tumor immune response. Insight into mechanisms of tumor escape from interferon activity offers potential opportunities for combinatorial therapeutic interventions to improve the immune response to cancer. Such strategies are a major focus of Dr. Hargadon’s article, which can be accessed at: https://onlinelibrary.wiley.com/doi/10.1111/bjd.20608

Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published a Viewpoint article on SARS-CoV-2 vaccine hesitancy in the Journal of Global Health Reports. His article focuses on lack of perceived threat from COVID-19 as a commonly documented reason for vaccine hesitancy and highlights the need for improved public education about risk factors for severe COVID-19 as a means of increasing vaccine acceptance. Though many risk factors for COVID-19 complications are widely publicized, including age and certain underlying health conditions, other less visible risk factors for severe COVID-19 disease have emerged from several studies over the course of the pandemic. Dr. Hargadon’s article highlights in particular multiple defects in the interferon antiviral defense system as clinically silent, or “invisible,” risk factors for severe COVID-19. These defects include genetic mutations in interferon pathway genes and autoimmune blockade of interferon proteins as significant risk factors for COVID-19 disease complications, though patients harboring such defects are typically unaware of their presence since the anomalies do not produce any symptoms until one is infected with a highly virulent pathogen.

Named as such because they typically “interfere” with viral replication, interferons normally provide early protection against any viral infection, limiting the propagation of viruses in an infected host. In the case of a highly pathogenic virus like SARS-CoV-2, defects in this system allow the virus to replicate out of control and result in severe disease, and there is now strong evidence that many critically ill COVID-19 patients, but not those who experience mild disease, harbor defects in the interferon defense system. These data explain many of the previously unexplained cases of severe COVID-19 that occur in young patients or in those who do not exhibit visibly apparent risk factors for serious illness. Dr. Hargadon’s article brings attention to these “invisible” risk factors for severe COVID-19 and discusses the importance of improved public education efforts to increase awareness of COVID-19 risk factors that we cannot see in ourselves or in others as a way of overcoming misperceptions of COVID-19 disease risk and encouraging SARS-CoV-2 vaccine acceptance.

Dr. Hargadon’s article is available at: https://www.joghr.org/article/26142-educating-society-about-the-unseen-but-not-unknown-risk-factors-for-severe-covid-19-a-step-towards-overcoming-vaccine-hesitancy-through-a-more-info

Elliott Associate Professor of Biology Dr. Kristian M. Hargadon ’01 recently published an article highlighting a course-based research approach to improve student understanding of cancer genetics. The article, published in the Journal of Cancer Education, describes a course-based undergraduate research experience (CURE) developed by Dr. Hargadon for use in his Biology 201 – Genetics and Cell Biology course and specifically highlights the utility of this approach for improving undergraduate student understanding of 1) the hallmark properties of cancer progression and 2) the genetic aberrations that drive these hallmark properties of cancer cells. This CURE, which involves multi-week student analyses of patient tumor-derived DNA- and RNA-sequencing datasets from The Cancer Genome Atlas, utilizes a bioinformatics approach for educating students about both genomic and transcriptomic anomalies that contribute to altered behavior in tumor versus normal cells.

Together with a hands-on experimental CURE involving gene expression analyses in murine melanoma cell lines that was previously published by Dr. Hargadon in the journal Biochemistry and Molecular Biology Education in 2016, this new CURE will be incorporated into an Experiential Learning course offering for Hampden-Sydney College’s COMPASS Program in the Fall 2021 semester.

Dr. Hargadon’s Journal of Cancer Education article is available at: https://link.springer.com/article/10.1007/s13187-021-01962-y

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:

https://www.springer.com/gp/book/9781071612040

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:

https://www.cancergeneticsjournal.org/article/S2210-7762(21)00076-4/fulltext

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