scholarly journals Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

2017 ◽  
Author(s):  
Martin G. Dalin ◽  
Nora Katabi ◽  
Marta Persson ◽  
Ken-Wing Lee ◽  
Vladimir Makarov ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Nuclear Dna ◽  
De Novo ◽  
Genomic Analysis ◽  
Salivary Gland Cancer ◽  
Gene Fusions ◽  
Myoepithelial Carcinoma ◽  
Molecular Alterations ◽  
Molecular Features

AbstractMyoepithelial carcinoma (MECA) is an aggressive type of salivary gland cancer with largely unknown molecular features. MECA may arise de novo or result from oncogenic transformation of a pre-existing pleomorphic adenoma (MECA ex-PA). We comprehensively analyzed the molecular alterations in MECA with integrated genomic analyses. We identified a low mutational load (0.5/MB), but a high prevalence of fusion oncogenes (28/40 tumors; 70%). We foundFGFR1-PLAG1in 7 (18%) cases, and the novelTGFBR3-PLAG1fusion in 6 (15%) cases.TGFBR3-PLAG1was specific for MECA de novo tumors or the malignant component of MECA ex-PA, was absent in 723 other salivary gland tumors, and promoted a tumorigenic phenotype in vitro. We discovered other novelPLAG1fusions, includingND4-PLAG1,which is an oncogenic fusion between mitochondrial and nuclear DNA. One tumor harbored anMSN-ALKfusion, which was tumorigenic in vitro, and targetable with ALK inhibitors. Certain gene fusions were predicted to result in neoantigens with high MHC binding affinity. A high number of copy number alterations was associated with poorer prognosis. Our findings indicate that MECA is a fusion-driven disease, nominateTGFBR3-PLAG1as a hallmark of MECA, and provide a framework for future steps of diagnostic and therapeutic research in this lethal cancer.

scholarly journals Flexible Cobamide Metabolism in Clostridioides (Clostridium) difficile 630 Δerm

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Amanda N. Shelton ◽  
Xun Lyu ◽  
Michiko E. Taga
Keyword(s):  
De Novo ◽  
Aminolevulinic Acid ◽  
Genomic Analysis ◽  
Opportunistic Pathogen ◽  
Vitamin B ◽  
Uptake System ◽  
Human Gut ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides (Clostridium) difficile is an opportunistic pathogen known for its ability to colonize the human gut under conditions of dysbiosis. Several aspects of its carbon and amino acid metabolism have been investigated, but its cobamide (vitamin B12 and related cofactors) metabolism remains largely unexplored. C. difficile has seven predicted cobamide-dependent pathways encoded in its genome in addition to a nearly complete cobamide biosynthesis pathway and a cobamide uptake system. To address the importance of cobamides to C. difficile, we studied C. difficile 630 Δerm and mutant derivatives under cobamide-dependent conditions in vitro. Our results show that C. difficile can use a surprisingly diverse array of cobamides for methionine and deoxyribonucleotide synthesis and can use alternative metabolites or enzymes, respectively, to bypass these cobamide-dependent processes. C. difficile 630 Δerm produces the cobamide pseudocobalamin when provided the early precursor 5-aminolevulinic acid or the late intermediate cobinamide (Cbi) and produces other cobamides if provided an alternative lower ligand. The ability of C. difficile 630 Δerm to take up cobamides and Cbi at micromolar or lower concentrations requires the transporter BtuFCD. Genomic analysis revealed genetic variations in the btuFCD loci of different C. difficile strains, which may result in differences in the ability to take up cobamides and Cbi. These results together demonstrate that, like other aspects of its physiology, cobamide metabolism in C. difficile is versatile. IMPORTANCE The ability of the opportunistic pathogen Clostridioides difficile to cause disease is closely linked to its propensity to adapt to conditions created by dysbiosis of the human gut microbiota. The cobamide (vitamin B12) metabolism of C. difficile has been underexplored, although it has seven metabolic pathways that are predicted to require cobamide-dependent enzymes. Here, we show that C. difficile cobamide metabolism is versatile, as it can use a surprisingly wide variety of cobamides and has alternative functions that can bypass some of its cobamide requirements. Furthermore, C. difficile does not synthesize cobamides de novo but produces them when given cobamide precursors. A better understanding of C. difficile cobamide metabolism may lead to new strategies to treat and prevent C. difficile-associated disease.

scholarly journals Autophagy and salivary gland cancer: A putative target for salivary gland tumors

Tumor Biology ◽  
2020 ◽  
Vol 42 (12) ◽  
pp. 101042832098056
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Margarita Theodorakidou ◽  
Michalis V Karamouzis ◽  
Stamatios Theocharis
Keyword(s):  
Salivary Gland ◽  
Current Knowledge ◽  
Treatment Options ◽  
Treatment Strategies ◽  
In Vivo Studies ◽  
Salivary Gland Cancer ◽  
Number Of Patients ◽  
Salivary Gland Carcinomas

Salivary gland carcinomas are a group of heterogeneous tumors of different histological subtypes, presenting relatively low incidence but the entire variable of types. Although novel treatment options for salivary gland carcinomas patients’ outcomes have improved, the treatment of this type of cancer is still not standardized. In addition, a significant number of patients, with a lack of optimal treatment strategies, have reduced survival. In the last two decades, a plethora of evidence pointed to the importance of autophagy, an essential catabolic process of cytoplasmatic component digestion, in cancer. In vitro and in vivo studies highlight the importance of autophagy in salivary gland carcinomas development as a tumor suppressor or promoter mechanism. Despite the potential of autophagy in salivary gland carcinomas development, no therapies are currently available that specifically focus on autophagy modulation in salivary gland carcinomas. In this review, we summarize current knowledge and clinical trials in regard to the interplay between autophagy and the development of salivary gland carcinomas. Autophagy manipulation may be a putative therapeutic strategy for salivary gland carcinomas patients.

scholarly journals Case report of myoepithelial carcinoma of maxillary sinus

2020 ◽  
Vol 10 (1) ◽  
pp. 85-87
Author(s):  
Ahmad Liaquat ◽  
Nabeela Riaz ◽  
Arun Kumar Shah
Keyword(s):  
Salivary Gland ◽  
Case Report ◽  
Maxillary Sinus ◽  
De Novo ◽  
Minor Salivary Gland ◽  
Myoepithelial Carcinoma ◽  
Titanium Mesh ◽  
Total Maxillectomy ◽  
Orbital Floor Reconstruction ◽  
Rare Malignancy

Myoepithelial carcinoma of the salivary gland is extremely rare malignancy. It may arise ei­ther in recurrent or pre existing pleomorphic adenoma or de novo in salivary glands. We herein present the case report of 35 years old male patient who presented to us with myo­epithelial carcinoma of minor salivary gland of right maxillary sinus. Right total maxillectomy was done and orbital floor reconstruction was done with titanium mesh.

The Proteasome Inhibitor Bortezomib Induces Tongue, Pharynx and Salivary Gland Cancer Cells Death in Vitro and Delays Tumor Growth of Salivary Gland Cancer Cells Transplanted in Mice

2021 ◽  
Author(s):  
Monica Benvenuto ◽  
Sara Ciuffa ◽  
Chiara Focaccetti ◽  
Diego Sbardella ◽  
Sara Fazi ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Intraperitoneal Administration ◽  
Erbb Receptors ◽  
Salivary Gland Cancer

Abstract Head and neck cancer (HNC) has frequently an aggressive course for the development of resistance to standard chemotherapy. Thus, the use of innovative therapeutic drugs is being assessed. Bortezomib is a proteasome inhibitor with strong in vitro and in vivo anticancer effects. In vitro antitumoral activity of Bortezomib was investigated employing human pharynx (FaDu), tongue (SCC-15, CAL-27), salivary gland (A-253) cancer cell lines and a murine cell line (SALTO-5) originated from a salivary gland adenocarcinoma arising in BALB-neuT male mice transgenic for the oncogene neu. Bortezomib in vivo effects in BALB-neuT mice transplanted with murine SALTO-5 cells were also examined. Bortezomib inhibited cells proliferation, triggered apoptosis, modulated the expression and activation of pro-survival signal transduction pathways proteins activated by ErbB receptors and inhibited proteasome activity in vitro. Furthermore, intraperitoneal administration of Bortezomib delayed tumor growth of SALTO-5 cells transplanted in BALB-neuT mice and protracted mice survival. Our findings further support the use of Bortezomib for the treatment of HNC and reveal its ineffectiveness in counteracting the activation of deregulated specific signaling pathways in HNC cell lines when resistance to proteasome inhibition is developed.

scholarly journals Survival of salivary gland cancer stem cells requires mTOR signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathalia P. Andrade ◽  
Kristy A. Warner ◽  
Zhaocheng Zhang ◽  
Alexander T. Pearson ◽  
Andrea Mantesso ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Tumor Cells ◽  
Mucoepidermoid Carcinoma ◽  
Therapeutic Potential ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Salivary Gland Cancer ◽  
Self Renewal ◽  
Immunodeficient Mice

AbstractAdvanced salivary gland mucoepidermoid carcinoma (MEC) is a relentless cancer that exhibits resistance to conventional chemotherapy. As such, treatment for patients with advanced MEC is tipically radical surgery and radiotherapy. Facial disfigurement and poor quality of life are frequent treatment challenges, and many patients succumb to loco-regional recurrence and/or metastasis. We know that cancer stem-like cells (CSC) drive MEC tumorigenesis. The current study tests the hypothesis that MEC CSC are sensitive to therapeutic inhibition of mTOR. Here, we report a correlation between the long-term clinical outcomes of 17 MEC patients and the intratumoral expression of p-mTOR (p = 0.00294) and p-S6K1 (p = 0.00357). In vitro, we observed that MEC CSC exhibit constitutive activation of the mTOR signaling pathway (i.e., mTOR, AKT, and S6K1), unveiling a potential strategy for targeted ablation of these cells. Using a panel of inhibitors of the mTOR pathway, i.e., rapamycin and temsirolimus (mTOR inhibitors), buparlisib and LY294002 (AKT inhibitors), and PF4708671 (S6K1 inhibitor), we observed consistently dose-dependent decrease in the fraction of CSC, as well as inhibition of secondary sphere formation and self-renewal in three human MEC cell lines (UM-HMC-1,-3A,-3B). Notably, therapeutic inhibition of mTOR with rapamycin or temsirolimus induced preferential apoptosis of CSC, when compared to bulk tumor cells. In contrast, conventional chemotherapeutic drugs (cisplatin, paclitaxel) induced preferential apoptosis of bulk tumor cells and accumulation of CSC. In vivo, therapeutic inhibition of mTOR with temsirolimus caused ablation of CSC and downregulation of Bmi-1 expression (major inducer of stem cell self-renewal) in MEC xenografts. Transplantation of MEC cells genetically silenced for mTOR into immunodeficient mice corroborated the results obtained with temsirolimus. Collectively, these data demonstrated that mTOR signaling is required for CSC survival, and unveiled the therapeutic potential of targeting the mTOR pathway for elimination of highly tumorigenic cancer stem-like cells in salivary gland mucoepidermoid carcinoma.

scholarly journals SOURCES OF LARVAL SALIVARY GLAND SECRETION IN THE DIPTERAN CHIRONOMUS TENTANS

1969 ◽  
Vol 40 (1) ◽  
pp. 61-78 ◽  
Author(s):  
D. Doyle ◽  
H. Laufer
Keyword(s):  
Salivary Gland ◽  
De Novo ◽  
Salivary Secretion ◽  
Disc Electrophoresis ◽  
Protein Fractions ◽  
Chironomus Tentans ◽  
Salivary Gland Secretion ◽  
Larval Salivary Gland

The soluble proteins in the hemolymph, the salivary gland, and the salivary secretion of fourth instar Chironomus tentans were examined by disc electrophoresis in acrylamide gels. Of the 11 protein fractions detected in buffered saline extracts of the gland, 10 are present also in the hemolymph. Amino acid isotope incorporation experiments indicate that the protein fractions shared by the salivary gland and the hemolymph are not synthesized in the gland but are synthesized in other larval tissues. Immunochemical studies show that most of these proteins eventually are secreted from the gland. The salivary gland in vivo and in vitro is active in de novo protein synthesis. The protein synthesized tends to form large molecular weight aggregates. As demonstrated by radioautography, at least 80% of this protein is secreted from the 30 large cells forming most of the gland. The proteins synthesized in the salivary gland cannot be detected in the hemolymph. The results of this investigation are consistent with a mechanism of secretion formation involving both de novo synthesis of some secretion proteins and the selective uptake, transport, and secretion of hemal proteins by the salivary gland.

scholarly journals GENE-04. THE ONCOGENIC FUNCTIONS OF YAP1-GENE FUSIONS CAN BE INHIBITED BY DISRUPTION OF YAP1-TEAD INTERACTION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi98-vi98
Author(s):  
Frank Szulzewsky ◽  
Pia Hoellerbauer ◽  
Hua-Jun Wu ◽  
P J Cimino ◽  
Franziska Michor ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Point Mutations ◽  
Tumor Formation ◽  
In Vitro Assays ◽  
Gene Fusions ◽  
Genetic Ablation ◽  
Molecular Features ◽  
Cancer Types

Abstract Supratentorial ependymoma can be sub-stratified into clinically relevant subtypes characterized by distinct molecular features. The subtype defined by high YAP1 activity harbored two distinct YAP1 gene fusions, YAP1-MAMLD1 and YAP1-FAM118B. In addition, YAP1 gene fusions have been detected in several other cancer types, including Epithelioid Hemangioendothelioma and Endocervical Adenocarcinoma. YAP1 is a key transcriptional co-activator and proto-oncogene that is negatively regulated by the Hippo pathway. Here, we show that both YAP1-MAMLD1 and YAP1-FAM118B, as well as additional YAP1 fusion genes found in other cancer types, are potent oncogenic drivers that cause tumor formation in the brain and the hindlimb in mice upon overexpression by somatic cell gene transfer. Using different in vitro assays, including Luciferase, RNA-, and ChIP Seq, we show that both the N-terminal YAP1 part and the C-terminal fusion partners exert activity. We can show that the YAP1 activity still relies on the binding to TEAD transcription factors, whereas the C terminal activity does not. Furthermore, the different fusion proteins have become independent from negative Hippo pathway signaling by constitutive nuclear localization and protection from degradation. In addition, by introducing point mutations and truncations to block the YAP1 and the MAMLD1 function we can show that the activity of both halves contributes to the oncogenic function of YAP1-MAMLD1. Using in vitro and in vivo assays we can show that pharmacological and genetic ablation of YAP-TEAD interaction diminishes the oncogenic potential of the fusions, indicating that this might be a potential therapeutic approach for these tumors in the future.

mTOR Inhibition Ablates Cisplatin-Resistant Salivary Gland Cancer Stem Cells

2020 ◽  
pp. 002203452096514
Author(s):  
T. Nakano ◽  
K.A. Warner ◽  
A.E. Oklejas ◽  
Z. Zhang ◽  
C. Rodriguez-Ramirez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Salivary Gland ◽  
Cancer Stem Cells ◽  
Mucoepidermoid Carcinoma ◽  
Salivary Gland Cancer ◽  
Mtor Inhibition ◽  
Platinum Based Chemotherapy ◽  
The Impact

Patients with advanced salivary gland mucoepidermoid carcinoma (MEC) are treated with surgery and radiotherapy, as current systemic therapies are largely ineffective. As such, current treatment frequently leads to poor long-term survival due to locoregional recurrence or metastases. We have shown that salivary gland cancer stem cells (CSCs) are resistant to platinum-based chemotherapy and drive tumor progression. The purpose of this study was to investigate the effect of therapeutic inhibition of mTOR (mechanistic target of rapamycin) on resistance of CSCs to cisplatin, a prototypic platinum-based chemotherapeutic agent. Viability assays determined the effect of several inhibitors of PI3k/mTOR signaling (e.g., temsirolimus, BKM120, AZD8055, PF4708671) and/or cisplatin on survival of human MEC cells. The impact of mTOR inhibitors and/or cisplatin on MEC stemness was examined with salisphere assays, flow cytometry for ALDH/CD44 (CSC markers for MEC), and Western blots for Bmi-1 expression (marker of stem cell self-renewal). Salivary gland MEC patient-derived xenografts were used to examine the effect of cisplatin and/or temsirolimus on CSCs in vivo. We observed that cisplatin induced mTOR and S6K1 phosphorylation, increased the number and size of MEC salispheres, and induced Bmi-1 expression and the fraction of CSCs in MEC models in vitro. Cisplatin also increased the fraction of CSCs in vivo. In contrast, mTOR inhibition (e.g., temsirolimus) blocked cisplatin-induced Bmi-1 expression and salisphere formation in vitro. Remarkably, temsirolimus slowed down tumor growth and decreased the fraction of CSCs ( P < 0.05) even in presence of cisplatin in a short-term in vivo experiment. Collectively, these results demonstrate that therapeutic inhibition of mTOR ablates cytotoxic-resistant CSCs, and they suggest that a combination of an mTOR inhibitor and platinum-based chemotherapy might be beneficial to patients with salivary gland mucoepidermoid carcinoma.

scholarly journals Restriction endonuclease activity induced by PBCV-1 virus infection of a Chlorella-like green alga.

1986 ◽  
Vol 6 (5) ◽  
pp. 1430-1439 ◽  
Author(s):  
Y N Xia ◽  
D E Burbank ◽  
L Uher ◽  
D Rabussay ◽  
J L Van Etten
Keyword(s):  
Enzyme Activity ◽  
Restriction Endonuclease ◽  
Green Alga ◽  
Nuclear Dna ◽  
De Novo ◽  
Dna Degradation ◽  
Endonuclease Activity ◽  
Modification System

An enzyme was isolated from a eucaryotic, Chlorella-like green alga infected with the virus PBCV-1 which exhibits type II restriction endonuclease activity. The enzyme recognized the sequence GATC and cleaved DNA 5' to the G. Methylation of deoxyadenosine in the GATC sequence inhibited enzyme activity. In vitro the enzyme cleaved host Chlorella nuclear DNA but not viral DNA because host DNA contains GATC and PBCV-1 DNA contains GmATC sequences. PBCV-1 DNA is probably methylated in vivo by the PBCV-1-induced methyltransferase described elsewhere (Y. Xia and J. L. Van Etten, Mol. Cell. Biol. 6:1440-1445). Restriction endonuclease activity was first detected 30 to 60 min after viral infection; the appearance of enzyme activity required de novo protein synthesis, and the enzyme is probably virus encoded. Appearance of enzyme activity coincided with the onset of host DNA degradation after PBCV-1 infection. We propose that the PBCV-1-induced restriction endonuclease participates in host DNA degradation and is part of a virus-induced restriction and modification system in PBCV-1-infected Chlorella cells.

scholarly journals Myoepithelial Carcinoma Arising in a Plasmacytoid Myoepithelioma of the Parotid Gland Synchronized with Melanoma: A Case Report and Review of the Literature

2021 ◽  
pp. 173-183
Author(s):  
Pamela Denisse Soberanis-Piña ◽  
Ricardo Fernández-Ferreira ◽  
Héctor Hugo Buerba-Vieregge ◽  
Edgar Varela-Santoyo ◽  
Jerónimo Rafael Rodriguez-Cid ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Parotid Gland ◽  
English Language ◽  
De Novo ◽  
Complete Response ◽  
Salivary Gland Neoplasm ◽  
Myoepithelial Carcinoma ◽  
Review Of The Literature ◽  
Nodal Dissection ◽  
Language Literature

Myoepithelial carcinoma, also known as malignant myoepithelioma, is considered an extremely rare (0.45–1%) malignant salivary gland neoplasm. Approximately 100 cases have been reported in the English-language literature on myoepithelial carcinoma. The majority of the myoepitheliomas described in the literature have been benign, and the malignant counterpart is considered rare (<1%). Such a tumor may appear de novo or rarely develop from a preexisting pleomorphic adenoma (<20%), and in exceedingly rare cases (<0.5%), it has arisen from a benign myoepithelioma (i.e., plasmacytoid myoepithelioma). To our knowledge, no case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma has been reported to date. The treatment of myoepithelial carcinoma has been mainly surgical, including wide excision with free margins, with or without nodal dissection. The roles of chemotherapy and radiotherapy have not yet been established. We report a case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma in a 40-year-old woman. In our case, a complete response was achieved with surgery followed by adjuvant chemotherapy based on carboplatin and paclitaxel concurrent with radiotherapy.

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