6 results on '"Vaishnavi Sambandam"'
Search Results
2. Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma
- Author
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Yi Liu, Ning Yin, Xue Wang, Andras Khoor, Vaishnavi Sambandam, Anwesha B. Ghosh, Zoe A. Fields, Nicole R. Murray, Verline Justilien, and Alan P. Fields
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Summary: Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2. Overexpression of PRKCI, SOX2, and ECT2 in the context of Trp53 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, PRKCI and SOX2 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas PRKCI and ECT2 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the PRKCI, SOX2, and ECT2 oncogenes represent a multigenic driver of LSCC. : Liu et al. report that three oncogenes, PRKCI, SOX2, and ECT2, which are coordinately amplified and overexpressed in lung squamous cell carcinoma (LSCC), can transform Trp53−/− mouse lung basal stem cells into tumors with histological and genomic features of LSCC and drive oncogenic signaling necessary to maintain a LSCC phenotype. Keywords: lung squamous cell carcinoma, LSCC, 3q26 copy number gain, CNG, PRKCI, SOX2, ECT2, lung basal stem cells, oncogenic transformation
- Published
- 2020
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3. Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma
- Author
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Verline Justilien, Yi Liu, Anwesha B. Ghosh, Xue Wang, Alan P. Fields, Vaishnavi Sambandam, Nicole R. Murray, Andras Khoor, Zoe A. Fields, and Ning Yin
- Subjects
0301 basic medicine ,Male ,Lung Neoplasms ,Transcription, Genetic ,Carcinogenesis ,Gene Dosage ,Context (language use) ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,SOX2 ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Humans ,Gene Silencing ,Lung cancer ,lcsh:QH301-705.5 ,Gene ,Protein Kinase C ,Cell Proliferation ,SOXB1 Transcription Factors ,Oncogenes ,medicine.disease ,Phenotype ,Gene Expression Regulation, Neoplastic ,Isoenzymes ,030104 developmental biology ,Cell Transformation, Neoplastic ,lcsh:Biology (General) ,Tumor progression ,Cancer research ,Carcinoma, Squamous Cell ,Chromosomes, Human, Pair 3 ,Stem cell ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Summary: Lung squamous cell carcinoma (LSCC) is a prevalent form of lung cancer exhibiting distinctive histological and genetic characteristics. Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors. We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2. Overexpression of PRKCI, SOX2, and ECT2 in the context of Trp53 loss is sufficient to transform mouse lung basal stem cells into tumors with histological and genomic features of LSCC. Functionally, PRKCI and SOX2 collaborate to activate an extensive transcriptional program that enforces a lineage-restricted LSCC phenotype, whereas PRKCI and ECT2 collaborate to promote oncogenic growth. Gene signatures indicative of PKCι-SOX2 and PKCι-ECT2 signaling activity are enriched in the classical subtype of human LSCC and predict distinct therapeutic vulnerabilities. Thus, the PRKCI, SOX2, and ECT2 oncogenes represent a multigenic driver of LSCC. : Liu et al. report that three oncogenes, PRKCI, SOX2, and ECT2, which are coordinately amplified and overexpressed in lung squamous cell carcinoma (LSCC), can transform Trp53−/− mouse lung basal stem cells into tumors with histological and genomic features of LSCC and drive oncogenic signaling necessary to maintain a LSCC phenotype. Keywords: lung squamous cell carcinoma, LSCC, 3q26 copy number gain, CNG, PRKCI, SOX2, ECT2, lung basal stem cells, oncogenic transformation
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- 2020
4. Genomic characterization of human papillomavirus-positive and -negative human squamous cell cancer cell lines
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Lerong Li, Xiayu Rao, Tuhina Mazumdar, Jeffrey N. Myers, Li Shen, Jing Wang, Mitchell J. Frederick, Yuanxin Xi, Curtis R. Pickering, Ameeta A. Patel, Faye M. Johnson, Frederico O. Gleber-Netto, Shaohua Peng, Vaishnavi Sambandam, Nene N. Kalu, and Yuan Qi
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0301 basic medicine ,Human Papillomavirus Positive ,Pathology ,medicine.medical_specialty ,Viral protein ,cervical cancer ,cell lines ,medicine.disease_cause ,head and neck squamous cell carcinoma ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Human papillomavirus ,human papillomavirus ,Cervical cancer ,Mutation ,business.industry ,Cancer ,virus diseases ,medicine.disease ,Head and neck squamous-cell carcinoma ,female genital diseases and pregnancy complications ,3. Good health ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,mutation ,business ,Research Paper - Abstract
// Nene N. Kalu 1, 6 , Tuhina Mazumdar 1 , Shaohua Peng 1 , Li Shen 2 , Vaishnavi Sambandam 1 , Xiayu Rao 2 , Yuanxin Xi 2 , Lerong Li 2 , Yuan Qi 2 , Frederico O. Gleber-Netto 3 , Ameeta Patel 3 , Jing Wang 2, 4 , Mitchell J. Frederick 5 , Jeffrey N. Myers 3, 4 , Curtis R. Pickering 3, 4 and Faye M. Johnson 1, 4 1 Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA 5 Department of Otolaryngology, Baylor College of Medicine, Houston, Texas, USA 6 Current/Present address: Lonza Viral Therapy, Houston, Texas, USA Correspondence to: Faye M. Johnson, email: fmjohns@mdanderson.org Keywords: human papillomavirus, cervical cancer, head and neck squamous cell carcinoma, cell lines, mutation Received: June 22, 2017 Accepted: August 21, 2017 Published: September 21, 2017 ABSTRACT Human cancer cell lines are the most frequently used preclinical models in the study of cancer biology and the development of therapeutics. Although anatomically diverse, human papillomavirus (HPV)-driven cancers have a common etiology and similar mutations that overlap with but are distinct from those found in HPV-negative cancers. Building on prior studies that have characterized subsets of head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESC) cell lines separately, we performed genomic, viral gene expression, and viral integration analyses on 74 cell lines that include all readily-available HPV-positive (9 HNSCC, 8 CESC) and CESC (8 HPV-positive, 2 HPV-negative) cell lines and 55 HPV-negative HNSCC cell lines. We used over 700 human tumors for comparison. Mutation patterns in the cell lines were similar to those of human tumors. We confirmed HPV viral protein and mRNA expression in the HPV-positive cell lines. We found HPV types in three CESC cell lines that are distinct from those previously reported. We found that cell lines and tumors had similar patterns of viral gene expression; there were few sites of recurrent HPV integration. As seen in tumors, HPV integration did appear to alter host gene expression in cell lines. The HPV-positive cell lines had higher levels of p16 and lower levels of Rb protein expression than did the HPV-negative lines. Although the number of HPV-positive cell lines is limited, our results suggest that these cell lines represent suitable models for studying HNSCC and CESC, both of which are common and lethal.
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- 2017
5. PDK1 mediates NOTCH1-mutated head and neck squamous carcinoma vulnerability to therapeutic PI3K/mTOR inhibition
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Qiuli Li, Li Shen, Ratnakar Singh, Mitchell J. Frederick, Jing Wang, Xiayu Rao, Shaohua Peng, Faye M. Johnson, Curtis R. Pickering, Vaishnavi Sambandam, Chenfei Huang, J.N. Myers, Pan Tong, and Tuhina Mazumdar
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Gene Expression ,Apoptosis ,Gene mutation ,Article ,law.invention ,Targeted therapy ,03 medical and health sciences ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,law ,Loss of Function Mutation ,Cell Line, Tumor ,Medicine ,Animals ,Humans ,Receptor, Notch1 ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Gene Editing ,Gene knockdown ,Dose-Response Relationship, Drug ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,TOR Serine-Threonine Kinases ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,medicine.disease ,Head and neck squamous-cell carcinoma ,Squamous carcinoma ,stomatognathic diseases ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,embryonic structures ,Cancer research ,cardiovascular system ,Suppressor ,sense organs ,biological phenomena, cell phenomena, and immunity ,CRISPR-Cas Systems ,business ,Signal Transduction - Abstract
Purpose: Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function. Experimental Design: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression. Results: PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1MUT) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in NOTCH1MUT but not NOTCH1WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1WT HNSCC but had little effect as single agents. Conclusions: Our findings suggest that NOTCH1MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1WT HNSCC to PI3K/mTOR pathway inhibitors.
- Published
- 2019
6. Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors
- Author
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Faye M. Johnson, Jing Wang, Shaohua Peng, Curtis R. Pickering, Jeffrey N. Myers, Ming Zhang, Pan Tong, Tuhina Mazumdar, Li Shen, Vaishnavi Sambandam, Nene N. Kalu, Ratnakar Singh, Lerong Li, and Mitchell J. Frederick
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0301 basic medicine ,Cancer Research ,Time Factors ,Apoptosis ,Cell Cycle Proteins ,0302 clinical medicine ,Urea ,Molecular Targeted Therapy ,Nuclear protein ,Smad4 Protein ,biology ,Kinase ,Pteridines ,Nuclear Proteins ,Cell cycle ,LIM Domain Proteins ,Protein-Tyrosine Kinases ,Tumor Burden ,G2 Phase Cell Cycle Checkpoints ,Wee1 ,Phenotype ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,RNA Interference ,Signal Transduction ,Genotype ,Mice, Nude ,Antineoplastic Agents ,Pyrimidinones ,Thiophenes ,Protein Serine-Threonine Kinases ,Transfection ,Article ,03 medical and health sciences ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Animals ,Humans ,CHEK1 ,Protein Kinase Inhibitors ,Cell Proliferation ,Dose-Response Relationship, Drug ,Cell growth ,Squamous Cell Carcinoma of Head and Neck ,medicine.disease ,Molecular biology ,Head and neck squamous-cell carcinoma ,Xenograft Model Antitumor Assays ,stomatognathic diseases ,Checkpoint Kinase 2 ,030104 developmental biology ,Pyrimidines ,Checkpoint Kinase 1 ,Mutation ,biology.protein ,ras Proteins ,Pyrazoles ,Protein Ajuba - Abstract
The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA, SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model. AJUBA protein expression was undetectable in most AJUBA-mutant HNSCC cell lines, and total PLK1 and Bora protein expression were decreased. Exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line partially rescued the phenotype of PLK1 inhibitor-induced apoptosis and decreased PLK1 substrate inhibition, suggesting a threshold effect in which higher drug doses are required to affect PLK1 substrate inhibition. PLK1 inhibition was an effective therapy for HNSCC in vitro and in vivo. However, biomarkers to guide such therapy are lacking. We identified AJUBA, SMAD4 and RAS mutations as potential candidate biomarkers of response of HNSCC to treatment with these mitotic inhibitors.
- Published
- 2017
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