Meera Nanjundan
Meera Nanjundan
Assistant Professor
Contact
Office: BSF 165
Phone: 813/974-8133
Email:
Links
Education
B.Sc (Honours), Queen’s University at Kingston, Ontario, CANADA, 1992-1996
Ph.D, University of Western Ontario, London, Ontario, CANADA, 1996-2001
Postdoctoral Fellow, The Scripps Research Institute, La Jolla, California, 2001-2003
Postdoctoral Fellow, MD Anderson Cancer Center, Houston, Texas, 2003-2007
Research Assistant Professor, MD Anderson Cancer Center, Houston, Texas, 2007
Research
A) Identification of 3Q Genomic Aberrations and Their Role in Lung Cancer Pathophysiology:
Based on published studies, CGH studies in lung cancer have shown profound chromosomal imbalances in the 3q region, which has consistently been found to be amplified in 77-80% of lung cancers. It has been recently reported through comprehensive analysis of 28 non-small cell lung carcinoma (NSCLC) cell models that chromosome 3q, although amplified in both subtypes (squamous carcinomas and adenocarcinomas) showed two distinct regions of alteration: 3q23-26 in squamous carcinomas and 3q22 in adenocarcinomas. The most consistent region of aberration across squamous lung cancers specifically is centered at 3q26.2. The consistent and reproducible nature of this event in a variety of carcinomas suggests that 3q26.2 harbors an oncogene(s) whose low-level amplification has a significant influence on tumor biology. However, the specific genes that drive the development of this amplicon are unclear. Further, whether these are the same genes in different cancer lineages (ovarian and lung) is also unknown. Both PIK3CA and PKCi copy number increases were reported to be increased in the majority of primary NSCLC tumors. The locus at 3q26.2 contains several potential oncogenes in addition to PKCi, including EVI1 and SnoN (most highly amplified at DNA and RNA level from our previous studies in ovarian tumorigenesis). Further, it is unknown whether the effect of a single gene or group of genes driving the selection of the amplicon contributes to lung tumorigenesis.
Our preliminary results of transcript levels in lung cancer cells indicate that although EVI1 is elevated (20-fold), GPCR150 (G-protein coupled receptor 150), which was only modestly increased in ovarian cancers, was even more remarkably amplified (75-fold) in lung cancer. These two genes are thus promising candidates to drive the 3q amplicon in lung cancers. Moreover, similar to our observations in ovarian cancer, we have identified several aberrant splice products of EVI1 in lung cancers, which have different functional outcomes compared to wild type EVI1. Strikingly, EVI1 mRNA levels in both ovarian and lung cancers are correlated with favorable patient prognosis, which may be as a result of the presence of the aberrant EVI1 splice forms and their resulting different functional outcomes. Thus, targeting these splice variants in lung cancers may have therapeutic value. Further, since over 60% of all drugs in current use target GPCR, targeting GPCR150 could provide an optimal target for therapy. GPCR150 is a G-protein coupled receptor in the putative unclassified Class A PCR (Orphan Receptor) with high similarity to serotonin, dopamine vertebrate type 2, lysophosphatidic acid (EDG7), as well as alpha adrenoreceptors type 1 receptors based on GLIDA analysis. The possible ligand binding partners of GPCR150 remain to be identified.
B) Role of Aberrant Splicing in Lung Cancer:
We have identified a number of genes within regions of genomic aberration in ovarian cancer as well as lung cancer that are aberrantly spliced as defined by the presence of frequent splice variants using cryptic splice sites rarely if ever used in normal cells. Alternative splicing of mRNA transcripts generates additional genomic complexity from the low number of genes present in the human genome. Specific alterations in splicing patterns in cancer may alter specific events during initiation and progression. Within the 3q26.2 genomically amplified region, EVI1 is highly and selectively amplified at the DNA, RNA, and protein level. Strikingly, EVI1 is aberrantly spliced resulting in production of MDS1/EVI1 (a readthrough encompassing EVI1 and the nearby MDS1 gene) and Del190-515 splice forms to a high frequency in >90% of advanced stage serous epithelial ovarian cancers as well as lung cancers. EVI1 and its splice variants play distinct roles during tumor initiation and progression depending on the cellular context based on altered signaling and functional outcomes. The effect of EVI1 is similar to the well-established dual effect of TGFb (inhibits growth inhibitor at early stages and promotes metastasis at late stages). Differential effects of the most highly expressed EVI1 splice variants on cellular function during tumor initiation and progression likely contribute to patient outcome. Thus, in addition to copy number aberrations, deregulated mRNA splicing leads to changes in protein function, likely altering prognosis and potentially response to chemotherapeutic agents. We propose that a detailed understanding of the regulatory mechanisms underlying aberrant splicing of EVI1 and other genes will lead to the development of molecular markers that will improve methods for early cancer detection, determining prognosis, and identifying novel targets. mRNA splicing is a critical step in post-transcriptional modification of RNA.
Since aberrant splicing is not limited to EVI1 at 3q26.2 but to additional amplified genes in ovarian and lung cancer, this appears to be a global phenomenon. The mechanisms responsible for these tumor-specific changes currently remain undefined and thus, the proposed studies are likely to provide a mechanistic basis for the investigation of genomically amplified genes associated with aberrant splicing. The cancer genome atlas project which will perform whole genome Exon array analysis in multiple cancers including lung will likely identify differential splicing patterns, establish genes participating in various steps of lung cancer development, and reveal the consequences of their dysregulated splicing.
C) Proteomic Characterization of Proliferative and Bioenergetic Pathways by Reverse Phase Protein Arrays in Lung Cancer:
Another area of current and proposed research investigation is in defining molecular signatures for targeted therapy of lung cancer. Although much progress has been made in lung cancer based on analysis of DNA aberrations and transcriptional profiling with these results beginning to impact patient care, proteins are the ultimate effectors of cellular outcomes, and functional proteomic data are essential to identification and validation of useful biomarkers for lung cancer. Aberrant activation of signaling pathways in lung cancer may occur as a result of loss, mutation, or hyperactivation of a variety of signaling molecules including those in the bioenergetic and proliferative pathways (ie. EGFR, RAS, PI3K/AKT, PTEN, and LKB1/AMPK). Thus, reverse phase protein lysate arrays (RPPA) offer an emerging approach to quantitative profiling of the levels and activation status of multiple proteins in lung cancer cells and patient samples. RPPA functions as a moderate throughput, quantitative, inexpensive, multiplexed ELISA with the potential to map protein levels as well as function in different intracellular pathways in a comprehensive, convenient, and sensitive manner. Thus, RPPA provides a practical approach to functional proteomics from the identification and validation of biomarkers for prognosis to prospective identification of patients likely to respond to particular therapies and monitoring response on therapy. The use of RPPA technology will allow determination of patient prognosis, predict response to particular therapeutics, determine biologically relevant doses, and identify early responders allowing direction to more effective therapies.
Current Courses
Recent Publications
Nanjundan M, Zhang F, Lahad J, Kuo W, Schmandt R, Smith-McCune K, Fishman D, Gray JW, Mills GB.
Overexpression of SnoN/SkiL, Amplified at the 3q26.2 Locus in Ovarian Cancers: Role in Ovarian Pathogenesis.
Molecular Oncology, 2008 Aug; 2(2):164-181.
Hennessy BT, Murph M, Nanjundan M, Carey M, Auersperg N, Almeida J, Coombes KR, Liu J, Lu Y, Gray JW, Mills GB.
Ovarian cancer: linking genomics to new target discovery and molecular markers--the way ahead.
Adv Exp Med Biol. 2008; 617:23-40.
Nanjundan M, Nakayama Y, Cheng KW, Lahad J, Liu J, Lu K, Kuo WL, Smith-McCune K, Fishman D, Gray JW, Mills GB.
Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer.
Cancer Res. 2007 Apr 1;67(7):3074-84.
Nanjundan M, Zhang F, Schmandt R, Smith-McCune K, Mills GB.
Identification of a novel splice variant of AML1b in ovarian cancer patients conferring loss of wild-type tumor suppressive functions.
Oncogene. 2007 Apr 19;26(18):2574-84.
Hennessy BT, Nanjundan M, Cheng KW, Nolden L, Mills GB.
Identification of remodeling and spacing factor 1 (rsf-1, HBXAP) at chromosome 11q13 as a putative oncogene in ovarian cancer.
Eur J Hum Genet. 2006 Apr;14(4):381-3.
Nanjundan M, Sun J, Zhao J, Zhou Q, Sims PJ, Wiedmer T.
Plasma membrane phospholipid scramblase 1 promotes EGF-dependent activation of c-Src through the epidermal growth factor receptor.
J Biol Chem. 2003 Sep 26;278(39):37413-8.
Wiedmer T, Zhao J, Nanjundan M, Sims PJ.
Palmitoylation of phospholipid scramblase 1 controls its distribution between nucleus and plasma membrane.
Biochemistry. 2003 Feb 11;42(5):1227-33.
Nanjundan M, Possmayer F.
Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase.
Am J Physiol Lung Cell Mol Physiol. 2003 Jan;284(1):L1-23.
Sun J, Nanjundan M, Pike LJ, Wiedmer T, Sims PJ.
Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor.
Biochemistry. 2002 May 21;41(20):6338-45.
Nanjundan M, Possmayer F.
Molecular cloning and expression of pulmonary lipid phosphate phosphohydrolases.
Am J Physiol Lung Cell Mol Physiol. 2001 Dec;281(6):L1484-93.
Nanjundan M, Possmayer F.
Pulmonary lipid phosphate phosphohydrolase in plasma membrane signalling platforms.
Biochem J. 2001 Sep 15;358(Pt 3):637-46.
Nanjundan M, Possmayer F.
Characterization of the pulmonary N-ethylmaleimide-insensitive phosphatidate phosphohydrolase.
Exp Lung Res. 2000 Jul-Aug;26(5):361-81.