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.
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.
•Smoking and copy number alteration was evaluated in head and neck cancer.•35 alterations correlate with smoking independent of human papillomavirus status.•Chromosome 11q13.4-11q13.4 amplification ...and 9p23.1/9p24.1 were most abundant.•16 genes from these regions form a signature that predicts poor patient outcome.•An 8-gene subset predicts increased odds of lymph node metastasis.
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.
Background:
Verrucous carcinoma of the larynx (VCL) is a rare form of laryngeal squamous cell carcinoma. We analyzed the National Cancer Database (NCDB) to examine national treatment pattern, ...identify factors associated with primary radiation therapy (RT), and compare outcomes in patients with Tis-T2 N0 VCL treated primary surgery and primary RT.
Methods:
We accessed the NCDB from 2004 to 2015 for patients with Tis-T2 N0 VCL and recorded the treatment modality employed. Multivariable logistic regression was used to identify predictors for radiation therapy. Cox regression was used to calculate hazard ratios for survival. A propensity score matched Kaplan–Meier analysis compared primary surgical treatment to definitive radiation.
Results:
We identified 732 patients with laryngeal verrucous carcinoma from the NCDB. The majority were cTis-T2 (87%) N0 (96%). We identified 286 vs. 110 Tis-T2N0 patients treated primary surgery and with definitive radiation, respectively, for the purpose of this study. Predictors of radiation were treatment at a community center, no insurance, and higher T stage. Cox regression identified increased age, higher comorbidity score, and government insurance as predictive of worse survival. Propensity matching revealed a trend toward worse survival with definitive radiation, with a median survival of 98 months compared to 143 months (
p
= 0.02). When including only T1-2 lesions, that is, invasive disease, the trend toward increased survival with surgery 98 months vs. 135 months (
p
= 0.08) persisted.
Conclusion:
The results of the present study support the use of surgery in the management of Tis-T2 N0 VCL when organ preservation is possible.
The staging of oropharyngeal squamous cell carcinoma has undergone key changes in the eighth edition of the American Joint Committee on Cancer Staging Manual, set to take effect January 1, 2018. The ...most significant change relates to the development of a novel staging system for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas, distinct from that for non-HPV-associated squamous cell carcinomas of the oropharynx. We describe the revised staging parameters and the rationale in support of the changes.
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