Jayaram S.,Institute of Bioinformatics |
Jayaram S.,Manipal University India |
Gupta M.K.,Institute of Bioinformatics |
Gupta M.K.,Manipal University India |
And 4 more authors.
Expert Review of Proteomics | Year: 2014
Glioblastoma multiforme (GBM) is one of the most aggressive and lethal forms of the primary brain tumors. With predominance of tumor heterogeneity and emergence of new subtypes, new approaches are needed to develop tissue-based markers for tumor typing or circulatory markers to serve as blood-based assays. Multi-omics data integration for GBM tissues would offer new insights on the molecular view of GBM pathogenesis useful to identify biomarker panels. On the other hand, mapping differentially expressed tissue proteins for their secretory potential through bioinformatics analysis or analysis of the tumor cell secretome or tumor exosomes would enhance our understanding of the tumor microenvironment and prospects for targeting circulatory biomarkers. In this review, the authors first present potential biomarker candidates for GBM that have been reported and then focus on plausible pipelines for multi-omic data integration to identify additional, high-confidence molecular panels for clinical applications in GBM. © 2014 Informa UK, Ltd.
Simple M.,Roswell Park Cancer Institute |
Simple M.,Vellore Institute of Technology |
Suresh A.,Mazumdar Shaw Center for Translational Research |
Suresh A.,Roswell Park Cancer Institute |
And 3 more authors.
Oral Oncology | Year: 2015
Oral squamous cell carcinoma (OSCC) has a high propensity for local failure, which is attributed to recurrence at the primary site or the development of second primary tumors (SPT). Field cancerization that refers to the existence of transformed cells in areas adjacent to the primary tumor, has been attributed to be one of the probable reasons underlying disease relapse. The carcinogenic process necessitates multiple molecular events for the transformation of a normal cell into a cancer cell. This implies that only the long-time residents of the epithelium, such as the stem cells, might be the candidates capable of accumulating these genetic hits. These transformed stem cells- the 'Cancer stem cells' (CSCs), are further known to be equipped with the properties of tumor initiation and migration, both of which are essential for orchestrating field cancerization. The concept that the CSCs might be responsible for field cancerization in OSCC has not been explored extensively. If the role of CSCs as the primary units of field cancerization process is established, their presence in the mucosa adjacent to the tumor may be an indicator for local recurrence and/or development of second primary tumors. In this review, we examine the available evidence in literature exploring the possibilities of CSCs driving the process of field cancerization and thereby being the underlying mechanism for disease recurrence and development of SPT. © 2015 Elsevier Ltd. All rights reserved.
Sirdeshmukh R.,Institute of Bioinformatics |
Sirdeshmukh R.,Mazumdar Shaw Center for Translational Research
Journal of Proteomics | Year: 2015
The Draft Maps of Human Proteome published in two independent articles provide a catalogue of proteins encoded in the human genome including missing proteins, based on large scale mass spectrometric analysis. Six months later, a Tissue-based Human Proteome Map was published which includes a study of expression and distribution of human proteins across tissues and cells using specific antibodies. Independently, in an ongoing global effort - the Chromosome centric, and Biology and Disease centric Human Proteome Project (C-HPP and B/D-HPP) initiated by the Human Proteome Organization aims to study in-depth human proteins and their variants in terms of biology and disease in a chromosome centric manner. Under this initiative, a consortium formed among five Asian research teams including India aims to study Chromosome 12 encoded proteins and their disease context. Together, the group has recently published the first series of 3 papers giving the overall vision and the initial contributions. While one of the draft maps of the human proteome is largely contributed by an Indian team, Indian researchers have significant role in the other two initiatives as well. These efforts will be pursued further as more teams join and more disease and biology components get incorporated. Biological significance: This article focuses on the complexity and challenges of deciphering human proteome and contribution of Indian researchers in the human proteome projects, including the on-going C-HPP.This article is part of a Special Issue entitled: Proteomics in India. © 2015 Elsevier B.V.
PubMed | Institute of Bioinformatics and Applied Biotechnology, Mazumdar Shaw Medical Center, Mazumdar Shaw Center for Translational Research, Institute of Bioinformatics and Strand Life science
Type: | Journal: Proteomics. Clinical applications | Year: 2016
Sample processing protocols that enable compatible recovery of differentially expressed transcripts and proteins are necessary for integration of the multiomics data applied in the analysis of tumors. In this pilot study, we compared two different isolation methods for extracting RNA and protein from laryngopharyngeal tumor tissues and the corresponding adjacent normal sections. In Method 1, RNA and protein were isolated from a single tissue section sequentially and in Method 2, the extraction was carried out using two different sections and two independent and parallel protocols for RNA and protein. RNA and protein from both methods were subjected to RNA-seq and iTRAQ-based LC-MS/MS analysis, respectively. Analysis of data revealed that a higher number of differentially expressed transcripts and proteins were concordant in their regulation trends in Method 1 as compared to Method 2. Cross-method comparison of concordant entities revealed that RNA and protein extraction from the same tissue section (Method 1) recovered more concordant entities that are missed in the other extraction method (Method 2) indicating heterogeneity in distribution of these entities in different tissue sections. Method 1 could thus be the method of choice for integrated analysis of transcriptome and proteome data.
PubMed | Mazumdar Shaw Center for Translational Research and Institute of Bioinformatics
Type: Journal Article | Journal: Journal of proteome research | Year: 2015
Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, is characterized by high rates of cell proliferation, migration, and invasion. New therapeutic strategies and targets are being continuously explored with the hope for better outcome. By overlaying transcriptomic and proteomic data from GBM clinical tissues, we identified 317 differentially expressed proteins to be concordant with the messenger RNAs (mRNAs). We used these entities to generate integrated regulatory information at the level of microRNAs (miRNAs) and their mRNA and protein targets using prediction programs or experimentally verified miRNA target mode in the miRWalk database. We observed 60% or even more of the miRNA-target pairs to be consistent with experimentally observed inverse expression of these molecules in GBM. The integrated view of these regulatory cascades in the contexts of cell proliferation and invasion networks revealed two-dimensional molecular interactions with regulatory and functional linkages (miRNAs and their mRNA-protein targets in one dimension; multiple miRNAs associated in a functional network in the second dimension). A total of 28 of the 35 differentially expressed concordant mRNA-protein entities represented in the proliferation network, and 51 of the 59 such entities represented in the invasion network, mapped to altered miRNAs from GBM and conformed to an inverse relationship in their expression. We believe the two-dimensional maps of gene expression changes enhance the strength of the discovery datasets derived from omics-based studies for their applications in GBM as well as tumors in general.
PubMed | Mazumdar Shaw Medical Center, Nizam's Institute of Medical Sciences, CSIR - Central Electrochemical Research Institute, Mazumdar Shaw Center for Translational Research and 2 more.
Type: | Journal: Scientific reports | Year: 2016
Diffuse astrocytoma (DA; WHO grade II) is a low-grade, primary brain neoplasm with high potential of recurrence as higher grade malignant form. We have analyzed differentially expressed membrane proteins from these tumors, using high-resolution mass spectrometry. A total of 2803 proteins were identified, 340 of them differentially expressed with minimum of 2 fold change and based on 2 unique peptides. Bioinformatics analysis of this dataset also revealed important molecular networks and pathways relevant to tumorigenesis, mTOR signaling pathway being a major pathway identified. Comparison of 340 differentially expressed proteins with the transcript data from Grade II diffuse astrocytomas reported earlier, revealed about 190 of the proteins correlate in their trends in expression. Considering progressive and recurrent nature of these tumors, we have mapped the differentially expressed proteins for their secretory potential, integrated the resulting list with similar list of proteins from anaplastic astrocytoma (WHO Grade III) tumors and provide a panel of proteins along with their proteotypic peptides, as a resource that would be useful for investigation as circulatory plasma markers for post-treatment surveillance of DA patients.
PubMed | Mazumdar Shaw Center for Translational Research, PHASE 2 International and Indian Institute of Science
Type: Journal Article | Journal: ACS applied materials & interfaces | Year: 2016
Recent studies have shown that three-dimensional (3D) culture environments allow the study of cellular responses in a setting that more closely resembles the in vivo milieu. In this context, hydrogels have become popular scaffold options for the 3D cell culture. Because the mechanical and biochemical properties of culture matrixes influence crucial cell behavior, selecting a suitable matrix for replicating in vivo cellular phenotype in vitro is essential for understanding disease progression. Gelatin methacrylate (GelMA) hydrogels have been the focus of much attention because of their inherent bioactivity, favorable hydration and diffusion properties, and ease-of-tailoring of their physicochemical characteristics. Therefore, in this study we examined the efficacy of GelMA hydrogels as a suitable platform to model specific attributes of breast cancer. We observed increased invasiveness in vitro and increased tumorigenic ability in vivo in breast cancer cells cultured on GelMA hydrogels. Further, cells cultured on GelMA matrixes were more resistant to paclitaxel treatment, as shown by the results of cell-cycle analysis and gene expression. This study, therefore, validates GelMA hydrogels as inexpensive, cell-responsive 3D platforms for modeling key characteristics associated with breast cancer metastasis, in vitro.
PubMed | Institute of Bioinformatics and Applied Biotechnology and Mazumdar Shaw Center for Translational Research
Type: Journal Article | Journal: Genes & cancer | Year: 2015
Laryngo-pharyngeal squamous cell carcinomas are one of the most common head and neck cancers. Despite the presence of a large body of information, molecular biomarkers are not currently used in the diagnosis, treatment and management of patients for this group of cancer. Here, we have profiled expression of genes and microRNAs of larynx and hypopharynx tumors using high-throughput sequencing experiments. We found that matrix metalloproteinases along with SCEL, CRNN, KRT4, SPINK5, and TGM3 among others have significantly altered expression in these tumors. Alongside gene expression, the microRNAs hsa-miR-139, hsa-miR-203 and the hsa-miR-424/503 cluster have aberrant expression in these cancers. Using target genes for these microRNAs, we found the involvement of pathways linked to cell cycle, p53 signaling, and viral carcinogenesis significant (P-values 10(-13), 10(-9) and 10(-7) respectively). Finally, using an ensemble machine-learning tool, we discovered a unique 8-gene signature for this group of cancers that differentiates the group from the other tumor subsites of head and neck region. We investigated the role of promoter methylation in one of these genes, WIF1, and found no correlation between DNA methylation and down-regulation of WIF1. We validated our findings of gene expression, 8-gene signature and promoter methylation using q-PCR, data from TCGA and q-MSP respectively. Data presented in this manuscript has been submitted to the NCBI Geo database with the accession number GSE67994.
PubMed | Institute of Bioinformatics and Applied Biotechnology, Mazumdar Shaw Center for Translational Research and Mazumdar Shaw Medical Center
Type: Journal Article | Journal: Molecular cancer research : MCR | Year: 2016
Oral tongue squamous cell carcinomas (OTSCC) are a homogenous group of aggressive tumors in the head and neck region that spread early to lymph nodes and have a higher incidence of regional failure. In addition, there is a rising incidence of oral tongue cancer in younger populations. Studies on functional DNA methylation changes linked with altered gene expression are critical for understanding the mechanisms underlying tumor development and metastasis. Such studies also provide important insight into biomarkers linked with viral infection, tumor metastasis, and patient survival in OTSCC. Therefore, we performed genome-wide methylation analysis of tumors (N = 52) and correlated altered methylation with differential gene expression. The minimal tumor-specific DNA 5-methylcytosine signature identified genes near 16 different differentially methylated regions, which were validated using genomic data from The Cancer Genome Atlas cohort. In our cohort, hypermethylation of MIR10B was significantly associated with the differential expression of its target genes NR4A3 and BCL2L11 (P = 0.0125 and P = 0.014, respectively), which was inversely correlated with disease-free survival (P = 9E-15 and P = 2E-15, respectively) in patients. Finally, differential methylation in FUT3, TRIM5, TSPAN7, MAP3K8, RPS6KA2, SLC9A9, and NPAS3 genes was found to be predictive of certain clinical and epidemiologic parameters.This study reveals a functional minimal methylation profile in oral tongue tumors with associated risk habits, clinical, and epidemiologic outcomes. In addition, NR4A3 downregulation and correlation with patient survival suggests a potential target for therapeutic intervention in oral tongue tumors. Data from the current study are deposited in the NCBI Geo database (accession number GSE75540). Mol Cancer Res; 14(9); 805-19. 2016 AACR.
PubMed | Institute of Bioinformatics and Applied Biotechnology, Mazumdar Shaw Center for Translational Research and Mazumdar Shaw Medical Center
Type: | Journal: F1000Research | Year: 2016
Oral tongue squamous cell carcinomas (OTSCC) are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population (<50yrs) is on the rise; many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs), indels, regions with loss of heterozygosity (LOH), and copy number variations (CNVs) from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV) infection and tumor recurrence. Apart from the frequent somatic variants harbored in TP53, CASP8, RASA1, NOTCH and CDKN2A genes, significant amplifications and/or deletions were detected in chromosomes 6-9, and 11 in the tumors. Variants in CASP8 and CDKN2A were mutually exclusive. CDKN2A, PIK3CA, RASA1 and DMD variants were exclusively linked to smoking, chewing, HPV infection and tumor stage. We also performed a whole-genome gene expression study that identified matrix metalloproteases to be highly expressed in tumors and linked pathways involving arachidonic acid and NF-k-B to habits and distant metastasis, respectively. Functional knockdown studies in cell lines demonstrated the role of CASP8 in a HPV-negative OTSCC cell line. Finally, we identified a 38-gene minimal signature that predicts tumor recurrence using an ensemble machine-learning method. Taken together, this study links molecular signatures to various clinical and epidemiological factors in a homogeneous tumor population with a relatively high HPV prevalence.