Vikki Noonan

Overexpression of DPAGT1 leads to aberrant N-glycosylation of E-cadherin and cellular discohesion in oral cancer

Cancer cells are frequently characterized by aberrant increases in protein N-glycosylation and by disruption of E-cadherin-mediated adherens junctions. The relationship between altered N-glycosylation and loss of E-cadherin adhesion in cancer, however, remains unclear. Previously, we reported that complex N-glycans on the extracellular domains of E-cadherin inhibited the formation of mature adherens junctions. Here, we examined whether dysregulated N-glycosylation was one of the underlying causes for cellular discohesion in oral cancer. We show that dense cultures of human salivary epidermoid carcinoma A253 cells exhibited elevated expression of DPAGT1, the gene that initiates protein N-glycosylation. Overexpression of DPAGT1 correlated with the production of E-cadherin-bearing complex N-glycans in nascent adherens junctions. Partial inhibition of DPAGT1 with small interfering RNA reduced the complex N-glycans of E-cadherin and increased the abundance of alpha-catenin and stabilizing proteins in adherens junctions. This was associated with the assembly of functional tight junctions. The inverse relationship between DPAGT1 expression and intercellular adhesion was a feature of oral squamous cell carcinoma. Oral squamous cell carcinomas displayed overexpression of DPAGT1 that correlated with diminished localization of E-cadherin and alpha-catenin at the sites of adherens junctions. Our studies show for the first time that DPAGT1 is an upstream regulator of E-cadherin N-glycosylation status and adherens junction composition and suggest that dysregulation of DPAGT1 causes disturbances in intercellular adhesion in oral cancer.

A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here, we show that the transcriptional regulators YAP (YAP1) and TAZ (WWTR1), which are key effectors of the Hippo pathway, drive protumorigenic signals in OSCC. Regions of premalignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro, and is required for OSCC tumor growth and metastasis in vivo. Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in protumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by The Cancer Genome Atlas (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology. Implications: This study defines a YAP/TAZ-regulated transcriptional program in OSCC and reveals novel roles for nuclear YAP/TAZ activity in the onset and progression of this cancer. Mol Cancer Res; 13(6); 957–68. ©2015 AACR.

Resorbable collagen membranes: histopathologic features

OBJECTIVE Resorbable collagen membranes (RCMs) are commonly used by oral surgeons, periodontists, and endodontists for multiple purposes. We report 6 cases of RCMs that did not resorb as expected and describe the histopathologic features. STUDY DESIGN Cases of an unusual fibrillar foreign material were noted in biopsy specimens curetted from bone. Hematoxylin-eosin and Masson trichrome stains were performed. Clinicians were contacted for detailed clinical information. RESULTS There were 3 men and 3 women. RCMs presented as hyalinized, paucicellular, delicate eosinophilic fibrils or a meshwork without a foreign body reaction. They were refractile and stained for Masson trichrome as expected. These RCMs persisted longer than expected (2-6 weeks) in 3 cases and may have retarded healing in 5 cases. CONCLUSIONS Although RCM is supposed to be fairly rapidly resorbable, this material sometimes persists within wound sites without any obvious foreign body reaction and may retard healing.

PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.

Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ), which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12), while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11). Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without the need for large-scale immunostaining experiments.

Granulomatous foreign body reaction to dermal cosmetic fillers with intraoral migration

OBJECTIVE We report intraoral granulomatous foreign body reactions in patients treated with calcium hydroxylapatite (CHA) or poly-l-lactic acid (PLA). STUDY DESIGN Clinical and histopathologic data were obtained from 25 patients who developed orofacial nodules or swelling after dermal filler injections. RESULTS All 25 patients were women aged 35 to 78 years (median, 55 years). All had a history of injection of CHA (n = 13) or PLA (n = 12) to the lips, nasolabial area, or mental area. Two patients developed cutaneous nodules at the sites of injections; all others presented with intraoral nodules (labial/buccal or vestibular mucosa) distant from the site of injections, suggestive of filler migration. Five of 21 cases presented with pain. Histopathologically, CHA presented as a diffuse mass of mauve-gray or beige, nonrefractile spherules, and PLA as rice- or spindle-shaped, geometric, refractile bodies within circumscribed nodules. CONCLUSIONS Cutaneous injections of CHA and PLA fillers may induce granulomatous reactions presenting as intraoral nodules distant from the injection sites.

Extraneural Sclerosing Perineurioma of the Buccal Mucosa: A Case Report and Clinicopathologic Review

The perineurioma is an infrequently encountered benign peripheral nerve sheath tumor composed of a clonal proliferation of perineurial cells. Rare cases of perineurioma have been reported in the oral cavity. An extraneural sclerosing perineurioma arising in the buccal mucosa of a 17-year-old male is presented. Histopathologically, the tumor is composed of a well circumscribed nodular proliferation of spindle cells arranged in a storiform growth pattern, in some areas subtly arranged around vascular channels. The tumor cells reveal positive immunostaining for epithelial membrane antigen (EMA), collagen type IV and vimentin, and negative immunostaining for S-100 protein, consistent with a perineurial origin. To the best of our knowledge, this case represents the first report of an extraneural sclerosing perineurioma involving the oral cavity.

Intraoral Spitz nevus: case report and literature review.

Spitz nevi account for approximately 1% of all melanocytic nevi of the skin in children. Although Spitz nevi often develop in the skin of the head and neck, intraoral Spitz nevi are rare. These nevi contain epithelioid and spindle cells and exhibit cytologic and architectural atypia when compared with routine melanocytic nevi, and may be mistaken for atypical Spitz tumor, Spitzoid melanoma, or conventional melanoma. Here, we report a Spitz nevus on the buccal mucosa of an 11-year-old boy. The tumor was composed of a proliferation of mostly epithelioid melanocytes with a smaller spindle cell component. The melanocytes were positive for S100, MART-1, and p16 proteins, with HMB-45-positive cells located only in the basal cell layer and superficial lamina propria. Less than 5% of the nuclei were positive for MIB-1, and there were no mitotic figures. We review the literature on 7 previously reported cases of Spitz nevi.

Radiolucent lesion of the posterior mandible.

j b e m s o s e d C A m t g c e meloblastic carcinoma is an uncommon, malignant dontogenic tumor with a predilection for occurrence n the posterior mandible. Only a limited number of ases have been reported. We report on a 16-year-old ale with ameloblastic carcinoma. This appears to be he first description of ameloblastic carcinoma of the andible treated with: 1) an initial bony reconstruction sing a microvascular free fibular flap and subsequent ugmentation with conventional autogenous bone rafts, 2) an initial soft-issue reconstruction using a mirovascular free-flap transfer and subsequent replaceent with keratinized tissue grafts, and 3) rehabilitation sing an implant-supported prosthesis.