Publications by authors named "Steven M Markwell"

7 Publications

  • Page 1 of 1

Copy number alterations identify a smoking-associated expression signature predictive of poor outcome in head and neck squamous cell carcinoma.

Cancer Genet 2021 Aug 28;256-257:136-148. Epub 2021 May 28.

Department of Biochemistry, Program in Cancer Cell Biology USA. Electronic address:

Cigarette smoking is a risk factor for the development of head and neck squamous cell carcinoma (HNSCC), partially due to tobacco-induced large-scale chromosomal copy-number alterations (CNAs). Identifying CNAs caused by smoking is essential in determining how gene expression from such regions impact tumor progression and patient outcome. We utilized The Cancer Genome Atlas (TCGA) whole genome sequencing data for HNSCC to directly identify amplified or deleted genes correlating with smoking pack-year based on linear modeling. Internal cross-validation identified 35 CNAs that significantly correlated with patient smoking, independent of human papillomavirus (HPV) status. The most abundant CNAs were chromosome 11q13.3-q14.4 amplification and 9p23.1/9p24.1 deletion. Evaluation of patient amplicons reveals four different patterns of 11q13 gene amplification in HNSCC resulting from breakage-fusion-bridge (BFB) events. . Predictive modeling identified 16 genes from these regions that denote poorer overall and disease-free survival with increased pack-year use, constituting a smoking-associated expression signature (SAES). Patients with altered expression of signature genes have increased risk of death and enhanced cervical lymph node involvement. The identified SAES can be utilized as a novel predictor of increased disease aggressiveness and poor outcome in smoking-associated HNSCC.
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http://dx.doi.org/10.1016/j.cancergen.2021.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273756PMC
August 2021

Disparate survival of late-stage male oropharyngeal cancer in Appalachia.

Sci Rep 2020 07 15;10(1):11612. Epub 2020 Jul 15.

Department of Biochemistry, Program in Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, P.O. Box 9300, Morgantown, WV, 26506, USA.

The United States Appalachian region harbors a higher cancer burden than the rest of the nation, with disparate incidence of head and neck squamous cell carcinomas (HNSCC), including oral cavity and pharynx (OC/P) cancers. Whether elevated HNSCC incidence generates survival disparities within Appalachia is unknown. To address this, HNSCC survival data for 259,737 tumors from the North American Association for Central Cancer Registries 2007-2013 cohort were evaluated, with age-adjusted relative survival (RS) calculated based on staging, race, sex, and Appalachian residence. Tobacco use, a primary HNSCC risk factor, was evaluated through the Behavioral Risk Factor Surveillance System from Appalachian states. Decreased OC/P RS was found in stage IV Appalachian white males within a subset of states. The survival disparity was confined to human papillomavirus (HPV)-associated oropharyngeal cancers, specifically the oropharynx subsite. This correlated with significantly higher smoking and male smokeless tobacco use in most Appalachian disparity states. Lower survival of Appalachian males with advanced-stage HPV-associated oropharyngeal cancers suggests pervasive tobacco consumption likely generates more aggressive tumors at HPV-associated oropharynx subsites than national averages. Comprehensive tobacco and HPV status should therefore be evaluated prior to considering treatment de-intensification regimens for HPV-associated oropharyngeal cancers in populations with high tobacco consumption.
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http://dx.doi.org/10.1038/s41598-020-68380-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363863PMC
July 2020

Methods for in vitro modeling of glioma invasion: Choosing tools to meet the need.

Glia 2020 11 5;68(11):2173-2191. Epub 2020 Mar 5.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Widespread tumor cell invasion is a fundamental property of diffuse gliomas and is ultimately responsible for their poor prognosis. A greater understanding of basic mechanisms underlying glioma invasion is needed to provide insights into therapies that could potentially counteract them. While none of the currently available in vitro models can fully recapitulate the complex interactions of glioma cells within the brain tumor microenvironment, if chosen and developed appropriately, these models can provide controlled experimental settings to study molecular and cellular phenomena that are challenging or impossible to model in vivo. Therefore, selecting the most appropriate in vitro model, together with its inherent advantages and limitations, for specific hypotheses and experimental questions achieves primary significance. In this review, we describe and discuss commonly used methods for modeling and studying glioma invasion in vitro, including platforms, matrices, cell culture, and visualization techniques, so that choices for experimental approach are informed and optimal.
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http://dx.doi.org/10.1002/glia.23813DOI Listing
November 2020

Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion.

Mol Cancer Res 2019 04 4;17(4):987-1001. Epub 2019 Jan 4.

Program in Cancer Cell Biology, Department of Biochemistry, West Virginia University, Morgantown, West Virginia.

Malregulation of the actin cytoskeleton enhances tumor cell motility and invasion. The actin-binding protein cortactin facilitates branched actin network formation through activation of the actin-related protein (Arp) 2/3 complex. Increased cortactin expression due to gene amplification is observed in head and neck squamous cell carcinoma (HNSCC) and other cancers, corresponding with elevated tumor progression and poor patient outcome. Arp2/3 complex activation is responsible for driving increased migration and extracellular matrix (ECM) degradation by governing invadopodia formation and activity. Although cortactin-mediated activation of Arp2/3 complex and invadopodia regulation has been well established, signaling pathways responsible for governing cortactin binding to Arp2/3 are unknown and potentially present a new avenue for anti-invasive therapeutic targeting. Here we identify casein kinase (CK) 2α phosphorylation of cortactin as a negative regulator of Arp2/3 binding. CK2α directly phosphorylates cortactin at a conserved threonine (T24) adjacent to the canonical Arp2/3 binding motif. Phosphorylation of cortactin T24 by CK2α impairs the ability of cortactin to bind Arp2/3 and activate actin nucleation. Decreased invadopodia activity is observed in HNSCC cells with expression of CK2α phosphorylation-null cortactin mutants, shRNA-mediated CK2α knockdown, and with the CK2α inhibitor Silmitasertib. Silmitasertib inhibits HNSCC collective invasion in tumor spheroids and orthotopic tongue tumors in mice. Collectively these data suggest that CK2α-mediated cortactin phosphorylation at T24 is critical in regulating cortactin binding to Arp2/3 complex and pro-invasive activity, identifying a potential targetable mechanism for impairing HNSCC invasion. IMPLICATIONS: This study identifies a new signaling pathway that contributes to enhancing cancer cell invasion. http://mcr.aacrjournals.org/content/molcanres/17/4/987/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445698PMC
April 2019

Methods of Academic Course Planning for Cancer Biology PhD Students to Enhance Knowledge of Clinical Oncology.

Cancer Res 2017 09 20;77(18):4741-4744. Epub 2017 Jul 20.

Department of Surgery and Office of Research and Graduate Education, West Virginia University, Morgantown, West Virginia.

Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821268PMC
September 2017

Tumor and stromal-based contributions to head and neck squamous cell carcinoma invasion.

Cancers (Basel) 2015 Feb 27;7(1):382-406. Epub 2015 Feb 27.

Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.

Head and neck squamous cell carcinoma (HNSCC) is typically diagnosed at advanced stages with evident loco-regional and/or distal metastases. The prevalence of metastatic lesions directly correlates with poor patient outcome, resulting in high patient mortality rates following metastatic development. The progression to metastatic disease requires changes not only in the carcinoma cells, but also in the surrounding stromal cells and tumor microenvironment. Within the microenvironment, acellular contributions from the surrounding extracellular matrix, along with contributions from various infiltrating immune cells, tumor associated fibroblasts, and endothelial cells facilitate the spread of tumor cells from the primary site to the rest of the body. Thus far, most attempts to limit metastatic spread through therapeutic intervention have failed to show patient benefit in clinic trails. The goal of this review is highlight the complexity of invasion-promoting interactions in the HNSCC tumor microenvironment, focusing on contributions from tumor and stromal cells in order to assist future therapeutic development and patient treatment.
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http://dx.doi.org/10.3390/cancers7010382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381264PMC
February 2015

Quantitative measurement of invadopodia-mediated extracellular matrix proteolysis in single and multicellular contexts.

J Vis Exp 2012 Aug 27(66):e4119. Epub 2012 Aug 27.

Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, USA.

Cellular invasion into local tissues is a process important in development and homeostasis. Malregulated invasion and subsequent cell movement is characteristic of multiple pathological processes, including inflammation, cardiovascular disease and tumor cell metastasis. Focalized proteolytic degradation of extracellular matrix (ECM) components in the epithelial or endothelial basement membrane is a critical step in initiating cellular invasion. In tumor cells, extensive in vitro analysis has determined that ECM degradation is accomplished by ventral actin-rich membrane protrusive structures termed invadopodia. Invadopodia form in close apposition to the ECM, where they moderate ECM breakdown through the action of matrix metalloproteinases (MMPs). The ability of tumor cells to form invadopodia directly correlates with the ability to invade into local stroma and associated vascular components. Visualization of invadopodia-mediated ECM degradation of cells by fluorescent microscopy using dye-labeled matrix proteins coated onto glass coverslips has emerged as the most prevalent technique for evaluating the degree of matrix proteolysis and cellular invasive potential. Here we describe a version of the standard method for generating fluorescently-labeled glass coverslips utilizing a commercially available Oregon Green-488 gelatin conjugate. This method is easily scaled to rapidly produce large numbers of coated coverslips. We show some of the common microscopic artifacts that are often encountered during this procedure and how these can be avoided. Finally, we describe standardized methods using readily available computer software to allow quantification of labeled gelatin matrix degradation mediated by individual cells and by entire cellular populations. The described procedures provide the ability to accurately and reproducibly monitor invadopodia activity, and can also serve as a platform for evaluating the efficacy of modulating protein expression or testing of anti-invasive compounds on extracellular matrix degradation in single and multicellular settings.
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http://dx.doi.org/10.3791/4119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606055PMC
August 2012
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