Faculty Bibliography
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757
Distinctive squamous cell carcinoma protein signatures [Meeting Abstract]
Squamous cell carcinoma (SQ) of the lung causes approximately 400,000 deaths per year worldwide, and no specifically targeted treatments yet exist. We used the SOMAscan proteomic platform (which measures 1129 proteins with a median limit of detection of 40 fM and 5% CV) in a broad-based analysis of serum and tissue samples to gain insight into the distinctive drivers of SQ malignant growth. We discovered unique SQ markers and pathways that show early expression of invasion and metastasis signals. Strong SQ signals were revealed. Our multi-center serum study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smoker and benign pulmonary nodule controls resulted in the discovery of 60 lung cancer biomarkers and the development of a 7-marker diagnostic panel. This panel was validated in two independent cohorts. The AUC for detection of SQ carcinoma was 0.93 in training and 0.89 in the Univ. of Heidelberg validation set (56 SQ cases/27 benign nodule controls). Performance was confirmed with an AUC of 0.87 in an independent validation cohort assembled by the EDRN (25 SQ cases/20 benign nodules/52 smoker controls). This non-invasive test could be used as an adjunct to CT to detect rapidly growing SQ tumors that are disproportionately missed as interval cancers in CT screening studies. In addition, we analyzed 68 NSCLC tumor and matched non-tumor tissue lysates. This study consisted of 49 adenocarcinoma (AD) and 19 SQ tumors, 88% of which were Stage I or II. Proteomic comparisons of tumor/non-tumor or AD/SQ tissue samples performed using the Mann-Whitney test identified 79 tumor markers. Differences between tumor and non-tumor tissue were dominated by inflammatory, apoptotic and cell proliferation proteins. Just as we observed in the serum studies, the most common pattern was an increasing difference in protein levels from non tumor to AD to SQ. Of note, 24% of the proteins were only markers in SQ. These SQ-only markers are enriched for angiogenesis, cell proliferation and cell adhesion f!
EMBASE:71378149
ISSN: 1078-0432
CID: 868252
The RON (MST1R)/MSP pathway is a potential therapeutic target in malignant pleural mesothelioma [Meeting Abstract]
ISI:000331494800079
ISSN: 0169-5002
CID: 852862
Mesothelioma
pp. 506-511
ISBN: 9781118589199
CID: 1928102
Seminars in Thoracic and Cardiovascular Surgery. Introduction [Editorial]
PMID: 25527008
ISSN: 1532-9488
CID: 4718362
Comprehensive molecular profiling of lung adenocarcinoma
ISI:000339566300025
ISSN: 0028-0836
CID: 5270632
CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells
Malignant pleural mesothelioma (MPM) is an asbestos-related thoracic malignancy that is characterized by late metastases, and resistance to therapeutic modalities. The toxic side-effects of MPM therapies often limit their clinical effectiveness, thus necessitating development of new agents to effectively treat and manage this disease in clinic. CARP-1 functional mimetics (CFMs) are a novel class of compounds that inhibit growth of diverse cancer cell types. Here we investigated MPM cell growth suppression by the CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited MPM cell growth, in vitro, in part by stimulating apoptosis. Apoptosis by CFM-4 involved activation of pro-apoptotic stress-activated protein kinases (SAPKs) p38 and JNK, elevated CARP-1 expression, cleavage of PARP1, and loss of the oncogene c-myc as well as mitotic cyclin B1. Treatments of MPM cells with CFM-4 resulted in depletion of NF-κB signaling inhibitor ABIN1 and Inhibitory κB (IκB)α and β, while increasing expression of pro-apoptotic death receptor (DR) 4 protein. CFM-4 enhanced expression of serine-phosphorylated podoplanin and cleavage of vimetin. CFMs also attenuated biological properties of the MPM cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Both podoplanin and vimentin regulate processes of cell motility and invasion, and their expression often correlates with metastatic disease, and poor prognosis. The fact that phosphorylation of serines in the cytoplasmic domain of podoplanin interferes with processes of cellular motility, CFM-4-dependent elevated phosphorylated podoplanin and cleavage of vimentin underscore a metastasis inhibitory property of these compounds, and suggest that CFMs and/or their future analogs have potential as anti-MPM agents.
PMCID:3943785
PMID: 24598827
ISSN: 1932-6203
CID: 4718332
Validation of a blood protein signature for non-small cell lung cancer
BACKGROUND: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. RESULTS: Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. CONCLUSIONS: Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
PMCID:4123246
PMID: 25114662
ISSN: 1542-6416
CID: 1131952
Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis
Dithiocarbamate compound Disulfiram (DSF) that binds with copper and functions as an inhibitor of aldehyde dehydrogenase is a Food and Drug Administration approved agent for treatment of alcoholism. Copper complexed DSF (DSF-Cu) also possesses anti-tumor and chemosensitizing properties; however, its molecular mechanisms of action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF-Cu and the molecular mechanisms involved. DSF-Cu inhibited growth of the murine as well as human MPM cells in part by increasing levels of ubiquitinated proteins. DSF-Cu exposure stimulated apoptosis in MPM cells that involved activation of stress-activated protein kinases (SAPKs) p38 and JNK1/2, caspase-3, and cleavage of poly-(ADP-ribose)-polymerase, as well as increased expression of sulfatase 1 and apoptosis transducing CARP-1/CCAR1 protein. Gene-array based analyses revealed that DSF-Cu suppressed cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF inhibited MPM cell growth and survival by upregulating cell cycle inhibitor p27Kip1, IGFBP7, and inhibitors of NF-κB such as ABIN 1 and 2 and Inhibitory κB (IκB)α and β proteins. DSF-Cu promoted cleavage of vimentin, as well as serine-phosphorylation and lysine-63 linked ubiquitination of podoplanin. Administration of 50 mg/kg DSF-Cu by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo. Although podoplanin expression often correlates with metastatic disease and poor prognosis, phosphorylation of serines in cytoplasmic domain of podoplanin has recently been shown to interfere with cellular motility and migration signaling. Post-translational modification of podoplanin and cleavage of vimentin by DSF-Cu underscore a metastasis inhibitory property of this agent and together with our in vivo studies underscore its potential as an anti-MPM agent.
PMCID:3972204
PMID: 24690739
ISSN: 1932-6203
CID: 4718342
Plasma Anti-Glycan Antibody Profiles Associated with Nickel level in Urine
Nickel (Ni) compounds are widely used in industrial and commercial products including household and cooking utensils, jewelry, dental appliances and implants. Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers, is the most common cause of contact dermatitis and has an extensive effect on the immune system. The purpose of this study was two-fold: (i) to evaluate immune response to the occupational exposure to nickel measured by the presence of anti-glycan antibodies (AGA) using a new biomarker-discovery platform based on printed glycan arrays (PGA), and (ii) to evaluate and compile a sequence of bioinformatics and statistical methods which are specifically relevant to PGA-derived information and to identification of putative "Ni toxicity signature". The PGAs are similar to DNA microarrays, but contain deposits of various carbohydrates (glycans) instead of spotted DNAs. The study uses data derived from a set of 89 plasma specimens and their corresponding demographic information. The study population includes three subgroups: subjects directly exposed to Nickel that work in a refinery, subjects environmentally exposed to Nickel that live in a city where the refinery is located and subjects that live in a remote location. The paper describes the following sequence of nine data processing and analysis steps: (1) Analysis of inter-array reproducibility based on benchmark sera; (2) Analysis of intra-array reproducibility; (3) Screening of data - rejecting glycans which result in low intra-class correlation coefficient (ICC), high coefficient of variation and low fluorescent intensity; (4) Analysis of inter-slide bias and choice of data normalization technique; (5) Determination of discriminatory subsamples based on multiple bootstrap tests; (6) Determination of the optimal signature size (cardinality of selected feature set) based on multiple cross-validation tests; (7) Identification of the top discriminatory glycans and their individual performance based on nonparametric univariate feature selection; (8) Determination of multivariate performance of combined glycans; (9) Establishing the statistical significance of multivariate performance of combined glycan signature. The above analysis steps have delivered the following results: inter-array reproducibility rho=0.920 +/- 0.030; intra-array reproducibility rho=0.929 +/- 0.025; 249 out of 380 glycans passed the screening at ICC>80%, glycans in selected signature have ICC >/= 88.7%; optimal signature size (after quantile normalization)=3; individual significance for the signature glycans p=0.00015 to 0.00164, individual AUC values 0.870 to 0.815; observed combined performance for three glycans AUC=0.966, p=0.005, CI=[0.757, 0947]; specifity=94.4%, sensitivity=88.9%; predictive (cross-validated) AUC value 0.836.
PMCID:3984841
PMID: 24737927
ISSN: 0974-276x
CID: 899372
Overexpression of EPH Receptor B2 in Malignant Mesothelioma Correlates with Oncogenic Behavior: Erratum (vol 8, pg 1203, 2013) [Correction]
ISI:000327420500030
ISSN: 1556-0864
CID: 687582
