Scott A Weed, PhD

Research Interests

The long-term research goal of the lab is centered on identifying novel molecular targets that can lead to new strategies reducing the burden of human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) in the underserved Appalachian region. Past work has combined mechanistic structure-function evaluation of select genes known or predicted to drive HNSCC invasion and regional lymph node involvement. More recent epidemiological work identified a survival disparity for oropharyngeal cancers in Appalachian subregions correlated with high levels of tobacco consumption and environmental water pollutant exposure from multiple natural and industrial sources. This multifactorial exposure elevates the overall carcinogenic insult to the at-risk Appalachian population. 

Behavioral and environmental factors leading to increased 11q13 amplification in Appalachian HNSCC. Risk factors enriched and/or specific to Appalachian HNSCC are shown on the left, with confirmed or suspected double strand DNA breakage agents involved in 11q13 amplification associated with each factor. The combined effect on the disparity population is anticipated to enhance the breakage-fusion-bridge cycle leading to 11q13 amplification and poorer overall survival as shown by survival analysis of a national cohort.

Ongoing project in the lab cover two main areas:

1. Determining the role of overexpressed chromosome 11q13 genes in Appalachian HNSCC

As a first step towards identifying the underlying molecular mechanisms driving disparate Appalachian HNSCC survival, we conducted an informatic analysis of HPV-negative cancers and patient smoking status. The majority of genes correlated with elevated patient smoking in HPV-negative HNSCC map to the chromosome 11q13 region. Chromosome 11q13 is amplified in over 25% of all HNSCC and is the most frequent copy number alteration in this cancer, long known to be associated with poor clinical characteristics and reduced patient survival. Overexpression of genes from the 11q13 amplicon predict reduced survival and increased cervical lymph node metastasis, constituting a Smoking-associated Overexpression Signature (SAES). While the oncogenic roles of some genes within the SAES are well-characterized, several SAES genes have not been evaluated. The goal of this project is to determine the role of these non-characterized SAES genes in driving HNSCC progression.

2. Evaluating overexpressed 11q13 transcripts as competitive endogenous RNAs  

Several non-protein coding RNA transcripts or transcript regions have been shown to bind to micro(mi)RNAs, reducing the number of specific miRNAs in the cytoplasm responsible for targeting transcripts for homeostatic miRNA-induced degradation. In cancer, such competing endogenous (ce)RNA transcripts act to sequester miRNAs that target transcripts encoding tumor suppressor proteins. ceRNA activity thus downregulates tumor suppressor transcripts that, in turn, can promote the oncogenic phenotype through persistence of tumor-promoting transcripts and subsequent translated oncoproteins.11q13 amplification results in overexpression of mRNA transcripts encoding SAES genes, raising the possibility that untranslated regions (UTRs) from these genes have the potential to act as ceRNAs in amplified HNSCC to enhance tumor progression. Ongoing work is geared towards testing such SAES transcripts for tumor promoting ceRNA activity.

Overexpressed ceRNA transcript activity from the 11q13 amplicon. Mechanisms of proposed 11q13 amplification-mediated ceRNA activity in regulating HPV-negative HNSCC oncoprotein expression. Transcriptional degradation pathways are shown for disomic (“normal”) and 11q13 amplified HNC^-. Overexpressed 11q13 transcript 3’-UTR microRNA binding sites serve as a decoy for oncoprotein transcript-targeting miRNAs. This activity allowing normally repressed oncoproteins to become expressed and contribute to tumor progression.

All projects in the lab employ a wide range of techniques including standard cell and molecular biological approaches, advanced cell and animal imaging techniques, in-depth bioinformatic analysis, Appalachian-derived tissue and cell models, and engineered tumor and transgenic animal model systems. Doctoral students in the laboratory can train in the Cancer Cell Biology or Biochemistry and Molecular Medicine graduate programs. Opportunities for undergraduate student research opportunities are abundant, with past and current students utilizing the WVU Cancer Institute Summer Undergraduate Research Program, the West Virginia IDeA network of Biomedical Research (WV-INBRE) summer program, The WVU Summer Undergraduate Research Experience (SURE), The WVU Research Apprenticeship Program (RAP), and/or the WVU EXCEL program. The laboratory also participates in several collaborative projects with other investigators via inter-departmental collaborations and through the Sara Crile Allen and James Frederick Allen Lung Cancer research program.

Publications

Most Recent:

Evaluation of the matrix metalloproteinase 9 (MMP9) inhibitor Andecaliximab as an Anti-invasive therapeutic in Head and neck squamous cell carcinoma 
Allen J., Hames R., Mastroianni N., Greenstein A., Weed SA. 
Oral Oncol. 2022 Sep;132:106008. doi: 10.1016/j.oraloncology.2022.106008. Epub 2022 Jul 6. PMID: 35803110

Copy number alterations identify a smoking-associated expression signature predictive of poor outcome in head and neck squamous cell carcinoma.
Papenberg BW, Ingles J, Gao S, Feng J, Allen JL, Markwell SM, Interval ET, Montague PA, Wen S, Weed SA.
Cancer Genet. 2021 Aug;256-257:136-148. doi: 10.1016/j.cancergen.2021.05.011. Epub 2021 May 28.
PMC8273756.

Disparate survival of late-stage male oropharyngeal cancer in Appalachia.
Papenberg BW, Allen JL, Markwell SM, Interval ET, Montague PA, Johnson CJ, Weed SA.
Sci Rep. 2020 Jul 15;10(1):11612. doi: 10.1038/s41598-020-68380-w.
PMC7363863.

Adaptation of the group A Streptococcus adhesin Scl1 to bind fibronectin type III repeats within wound-associated extracellular matrix: implications for cancer therapy.
McNitt DH, Choi SJ, Allen JL, Hames RA, Weed SA, Van De Water L, Berisio R, Lukomski S.
Mol Microbiol. 2019 Sep;112(3):800-819. doi: 10.1111/mmi.14317. Epub 2019 Jun 12.
PMC6736723.

Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion.
Markwell S, Ammer A, Interval E, Allen J, Papenberg B, Hames R, Castaño J, Schafer D, Weed S
Mol Cancer Res. 2019 Apr;17(4):987-1001.
PMC6445698

High-frequency ultrasound imaging of mouse cervical lymph nodes.
Walk EL, McLaughlin SL, Weed SA.
J Vis Exp. 2015; (101): e52718.
PMC4545045

Tumor and stromal-based contributions to head and neck squamous cell carcinoma invasion.
Markwell SM, Weed SA.
Cancers (Basel). 2015; 7(1): 382-406.
PMC4381264

Use of high frequency ultrasound to monitor cervical lymph node alterations in mice.
Walk EL, McLaughlin SL, Coad JE, Weed SA.
PLoS One. 2014; 9(6): e100185.
PMC4067293

SRChing for the substrates of Src.
Reynolds AB, Kanner SB, Bouton AH, Schaller MD, Weed SA, Flynn DC, Parsons JT.
Oncogene. 2014; 33(37): 4537-4547.

NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis.
McLaughlin SL, Ice RJ, Rajulapati A, Kozyulina PY, Livengood RH, Kozyreva VK, Loskutov YV, Culp M, Weed SA, Ivanov AV, Pugacheva EN.
Mol Cancer Res. 2014; 12(1): 69-81.
PMC3946989

NEDD9 regulates actin dynamics through cortactin deacetylation in an AURKA/HDAC6-dependent manner.
Kozyreva VK, McLaughlin SL, Livengood RH, Calkins RA, Kelley LC, Rajulapati A, Ice RJ, Smolkin MB, Weed SA, Pugacheva EN.
Mol Cancer Res. 2014; 12(5): 681-693.
PMC4020952

Metastatic MTLn3 and non-metastatic MTC adenocarcinoma cells can be differentiated by Pseudomonas aeruginosa.
Novotny MJ, Bridge DR, Martin KH, Weed SA, Wysolmerski RB, Olson JC.
Biol Open. 2013; 2(9): 891-900.
PMC3773335

Phosphorylation of the alternative mRNA splicing factor 45 (SPF45) by Clk1 regulates its splice site utilization, cell migration and invasion.
Liu Y, Conaway L, Rutherford BJ, Al-Ayoubi AM, Thompson BA, Zheng H, Weed SA, Eblen ST.
Nucleic Acids Res. 2013; 41(9): 4949-4962.
PMC3643583

Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop.
Hayes KE, Walk EL, Ammer AG, Kelley LC, Martin KH, Weed SA.
Oncogene. 2013; 32(40): 4766-4777.
PMC3896120

Effects of tobacco smoking and nicotine on cancer treatment.
Petros WP, Younis IR, Ford JN, Weed SA.
Pharmacotherapy. 2012; 32(10): 920-931.
PMC3499669