Sandra Orsulic

University of California, Los Angeles, Los Ángeles, California, United States

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Publications (71)554.24 Total impact

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    ABSTRACT: ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high grade serous ovarian carcinoma (HGSOC). Here we sought to determine if high levels of the ADAM12 protein and/or mRNA are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were TGFβ signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFβ signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Carcinogenesis 04/2015; DOI:10.1093/carcin/bgv059 · 5.27 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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    ABSTRACT: Cells deficient in argininosuccinate synthetase (ASS) must absorb the arginine they need for growth from circulating blood. Treatment with pegylated arginine deiminase (ADI-PEG 20) selectively eliminates arginine from the circulation and has shown some efficacy against ASS-deficient tumors including small cell lung cancer (SCLC). We sought to assess ASS expression in a cohort of high-grade pulmonary neuroendocrine carcinomas (PNEC) which include SCLC and large cell neuroendocrine carcinoma (LCNEC). Sixty-nine PNEC (49 SCLC and 20 LCNEC) were retrieved from our pathology archives. Formalin-fixed paraffin-embedded sections of the 54 primary tumors, 15 metastases and appropriate positive and negative controls were immunostained using an ASS-specific monoclonal antibody. Positive staining in <30 % of the tumor was scored as weak; staining in ≥30 % of the tumor was scored as strong. The absence of staining in the tumor was recorded as ASS negative. 58 % of the PNEC including 61.2 % of the SCLC and 50 % of the LCNEC were ASS negative. These ASS-negative tumors included 63 % of the primary and 40 % of the metastatic lesions tested. More than 50 % of the high-grade PNEC tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. PNEC comprise about 25 % of primary lung cancers and have a 5-year overall survival of only 5-10 %, underscoring the need for new and more effective therapies. Immunostaining for ASS has potential to improve the selection of patients with PNEC for arginine deprivation therapy with ADI-PEG 20.
    Journal of Cancer Research and Clinical Oncology 12/2014; DOI:10.1007/s00432-014-1904-z · 3.01 Impact Factor
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    ABSTRACT: High-grade serous ovarian cancers (HGSOC) are genomically complex, heterogeneous cancers with a high mortality rate, due to acquired chemoresistance and lack of targeted therapy options. Cyclin-dependent kinase inhibitors (CDKi) target the retinoblastoma (RB) signaling network, and have been successfully incorporated into treatment regimens for breast and other cancers. Here, we have compared mechanisms of response and resistance to three CDKi that target either CDK4/6 or CDK2 and abrogate E2F target gene expression. We identify CCNE1 gain and RB1 loss as mechanisms of resistance to CDK4/6 inhibition, whereas receptor tyrosine kinase (RTK) and RAS signaling is associated with CDK2 inhibitor resistance. Mechanistically, we show that ETS factors are mediators of RTK/RAS signaling that cooperate with E2F in cell cycle progression. Consequently, CDK2 inhibition sensitizes cyclin E1-driven but not RAS-driven ovarian cancer cells to platinum-based chemotherapy. In summary, this study outlines a rational approach for incorporating CDKi into treatment regimens for HGSOC.
    Oncotarget 12/2014; · 6.63 Impact Factor
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    ABSTRACT: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2,185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. Copyright © 2014. Published by Elsevier Inc.
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    ABSTRACT: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24:308-16. DOI:10.1158/1055-9965.EPI-14-0532 · 4.32 Impact Factor
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    ABSTRACT: The current standard of care for epithelial ovarian cancer does not discriminate between different histologic subtypes (serous, clear cell, endometrioid and mucinous) despite the knowledge that ovarian carcinoma subtypes do not respond uniformly to conventional platinum/taxane-based chemotherapy. Exploiting addictions and vulnerabilities in cancers with distinguishable molecular features presents an opportunity to develop individualized therapies that may be more effective than the current ‘one size fits all' approach. One such opportunity is arginine depletion therapy with pegylated arginine deiminase, which has shown promise in several cancer types that exhibit low levels of argininosuccinate synthetase including hepatocellular and prostate carcinoma and melanoma. Based on the high levels of argininosuccinate synthetase previously observed in ovarian cancers, these tumours have been considered unlikely candidates for arginine depletion therapy. However, argininosuccinate synthetase levels have not been evaluated in the individual histologic subtypes of ovarian carcinoma. The current study is the first to examine the expression of argininosuccinate synthetase at the mRNA and protein levels in large cohorts of primary and recurrent ovarian carcinomas and ovarian cancer cell lines. We show that the normal fallopian tube fimbria and the majority of primary high-grade and low-grade serous ovarian carcinomas express high levels of argininosuccinate synthetase, which tend to further increase in recurrent tumours. In contrast to the serous subtype, non-serous ovarian carcinoma subtypes (clear cell, endometrioid and mucinous) frequently lack detectable argininosuccinate synthetase expression. The in vitro sensitivity of ovarian cancer cell lines to arginine depletion with pegylated arginine deiminase was inversely correlated with argininosuccinate synthetase expression. Our data suggest that the majority of serous ovarian carcinomas are not susceptible to therapeutic intervention with arginine deiminase while a subset of non-serous ovarian carcinoma subtypes are auxotrophic for arginine and should be considered for clinical trials with pegylated arginine deiminase.
    10/2014; 1(1). DOI:10.1002/cjp2.4
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    ABSTRACT: Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear.
    Annals of Surgical Oncology 08/2014; DOI:10.1245/s10434-014-3980-3 · 3.94 Impact Factor
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    ABSTRACT: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
    Molecular Nutrition & Food Research 07/2014; DOI:10.1002/mnfr.201400068 · 4.91 Impact Factor
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    ABSTRACT: Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA–mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan–Meier analysis and log-rank tests. All statistical tests were two-sided. Results Associations with outcome were observed with ABC transporters of the “A” subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e−6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Conclusions Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
    JNCI Journal of the National Cancer Institute 06/2014; DOI:10.1093/jnci/dju149 · 15.16 Impact Factor
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    ABSTRACT: Objective : Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers. Methods : The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo. Results : The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4 + depletion combined with PLD significantly prolonged overall survival (p = 0.0204) in BRCA1- tumor-bearing mice. Conclusion : Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4 + T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations.
    Gynecologic Oncology 06/2014; DOI:10.1016/j.ygyno.2014.03.565 · 3.69 Impact Factor
  • Gynecologic Oncology 06/2014; 133:115-116. DOI:10.1016/j.ygyno.2014.03.305 · 3.69 Impact Factor
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    ABSTRACT: The current standard of care for epithelial ovarian cancer does not discriminate between different histologic subtypes (serous, clear cell, endometrioid and mucinous) despite the knowledge that ovarian carcinoma subtypes do not respond uniformly to conventional platinum/taxane-based chemotherapy. Exploiting addictions and vulnerabilities in cancers with distinguishable molecular features presents an opportunity to develop individualized therapies that may be more effective than the current ‘one size fits all’ approach. One such opportunity is arginine depletion therapy with pegylated arginine deiminase, ADI-PEG 20, which has shown promise in several cancer types that exhibit low levels of argininosuccinate synthetase (ASS1) including hepatocellular and prostate carcinoma and melanoma. Based on the high levels of ASS1 previously observed in ovarian cancers, these tumors have been considered unlikely candidates for arginine depletion therapy. However, ASS1 levels have not been evaluated in the individual histologic subtypes of ovarian carcinoma. The current study is the first to examine the expression of ASS1 at the mRNA and protein levels in large cohorts of primary and recurrent ovarian carcinomas and ovarian cancer cell lines. We show that the normal fallopian tube fimbria and the majority of primary high-grade and low-grade serous ovarian carcinomas express high levels of ASS1, which tend to further increase in recurrent tumors. In contrast to the serous subtype, non-serous ovarian carcinoma subtypes (clear cell, endometrioid and mucinous) frequently lack detectable ASS1 expression. The in vitro sensitivity of ovarian cancer cell lines to arginine depletion with ADI-PEG 20 was inversely correlated with ASS1 expression. Our data suggest that the majority of serous ovarian carcinomas are not susceptible to therapeutic intervention with arginine deiminase while a subset of non-serous ovarian carcinoma subtypes are auxotrophic for arginine and should be considered for clinical trials with ADI-PEG 20.
    Journal of Clinical Pathology 06/2014; DOI:10.1002/cjp2.00004 · 2.55 Impact Factor
  • Clinical Cancer Research 05/2014; 19(19_Supplement):B48-B48. DOI:10.1158/1078-0432.OVCA13-B48 · 8.19 Impact Factor
  • Clinical Cancer Research 05/2014; 19(19_Supplement):IA11-IA11. DOI:10.1158/1078-0432.OVCA13-IA11 · 8.19 Impact Factor
  • Dong-Joo Cheon, Sandra Orsulic
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    ABSTRACT: Keywords: collagen • metastasis • ovarian cancer • poor prognosis • stroma • ten-gene biomarker This editorial article discuss our recent discovery of the collagen-remodeling gene signature: 1. Current challenges in ovarian cancer management 2. Identification of the ten-gene biomarker panel 3. Tumor–stroma interaction: Achilles’ heel of ovarian cancer? 4. Conclusion & future perspective
    Biomarkers in Medicine 04/2014; 8(4):523-6. DOI:10.2217/bmm.14.16 · 2.86 Impact Factor
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    ABSTRACT: Although dendritic cell (DC) vaccines are considered to be promising treatments for advanced cancer, their production and administration is costly and labor-intensive. We developed a novel immunotherapeutic agent that links a single-chain antibody variable fragment (scFv) targeting mesothelin (MSLN), which is overexpressed on ovarian cancer and mesothelioma cells, to Mycobacterium tuberculosis (MTB) heat shock protein 70 (Hsp70), which is a potent immune activator that stimulates monocytes and DCs, enhances DC aggregation and maturation and improves cross-priming of T cells mediated by DCs. Binding of this fusion protein with MSLN on the surface of tumor cells was measured by flow cytometry and fluorescence microscopy. The therapeutic efficacy of this fusion protein was evaluated in syngeneic and orthotopic mouse models of papillary ovarian cancer and malignant mesothelioma. Mice received 4 intraperitoneal (ip) treatments with experimental or control proteins post ip injection of tumor cells. Ascites-free and overall survival time was measured. For the investigation of anti-tumor T-cell responses, a time-matched study was performed. Splenocytes were stimulated with peptides, and IFNgamma- or Granzyme B- generating CD3+CD8+ T cells were detected by flow cytometry. To examine the role of CD8+ T cells in the antitumor effect, we performed in vivo CD8+ cell depletion. We further determined if the fusion protein increases DC maturation and improves antigen presentation as well as cross-presentation by DCs. We demonstrated in vitro that the scFvMTBHsp70 fusion protein bound to the tumor cells used in this study through the interaction of scFv with MSLN on the surface of these cells, and induced maturation of bone marrow-derived DCs Use of this bifunctional fusion protein in both mouse models significantly enhanced survival and slowed tumor growth while augmenting tumor-specific CD8+ T-cell dependent immune responses. We also demonstrated in vitro and in vivo that the fusion protein enhanced antigen presentation and cross-presentation by targeting tumor antigens towards DCs. This new cancer immunotherapy has the potential to be cost-effective and broadly applicable to tumors that overexpress mesothelin.
    Journal of Hematology & Oncology 02/2014; 7(1):15. DOI:10.1186/1756-8722-7-15 · 4.93 Impact Factor
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    ABSTRACT: Succinate dehydrogenase (SDH) is a mitochondrial metabolic enzyme complex involved in both the electron transport chain and the citric acid cycle. SDH mutations resulting in enzymatic dysfunction have been found to be a predisposing factor in various hereditary cancers. Therefore, SDH has been implicated as a tumor suppressor. We identified that dysregulation of SDH components also occurs in serous ovarian cancer, particularly the SDH subunit SDHB. Targeted knockdown of Sdhb in mouse ovarian cancer cells resulted in enhanced proliferation and an epithelial-to-mesenchymal transition (EMT). Bioinformatics analysis revealed that decreased SDHB expression leads to a transcriptional upregulation of genes involved in metabolic networks affecting histone methylation. We confirmed that Sdhb knockdown leads to a hypermethylated epigenome that is sufficient to promote EMT. Metabolically, the loss of Sdhb resulted in reprogrammed carbon source utilization and mitochondrial dysfunction. This altered metabolic state of Sdhb knockdown cells rendered them hypersensitive to energy stress. These data illustrate how SDH dysfunction alters the epigenetic and metabolic landscape in ovarian cancer. By analyzing the involvement of this enzyme in transcriptional and metabolic networks, we find a metabolic Achilles' heel that can be exploited therapeutically. Analyses of this type provide an understanding how specific perturbations in cancer metabolism may lead to novel anticancer strategies.
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    ABSTRACT: To identify molecular prognosticators and therapeutic targets for high-grade serous epithelial ovarian cancers (EOC) using genetic analyses driven by biologic features of EOC pathogenesis. Ovarian tissue samples (n=172; 122 serous EOC, 30 other EOC, 20 normal/benign) collected prospectively from sequential patients undergoing gynecologic surgery were analyzed using RNA expression microarrays. Samples were classified based on expression of genes with potential relevance in ovarian cancer. Gene sets were defined using Rosetta Similarity Search Tool (ROAST) and analysis of variance (ANOVA). Gene copy number variations were identified by array comparative genomic hybridization. No distinct subgroups of EOC could be identified by unsupervised clustering, however, analyses based on based on genes correlated with periostin (POSTN) and estrogen receptor-alpha (ESR1) yielded distinct subgroups. When 95 high-grade serous EOC were grouped by genes based on ANOVA comparing ESR1/WT1 and POSTN/TGFBI samples, overall survival (OS) was significantly shorter for 43 patients with tumors expressing genes associated with POSTN/TGFBI compared to 52 patients with tumors expressing genes associated with ESR1/WT1 (median 30 versus 49 months, respectively; P=0.022). Several targets with therapeutic potential were identified within each subgroup. BRCA germline mutations were more frequent in the ESR1/WT1 subgroup. Proliferation-associated genes and TP53 status (mutated or wild-type) did not correlate with survival. Findings were validated using independent ovarian cancer datasets. Two distinct molecular subgroups of high-grade serous EOC based on POSTN/TGFBI and ESR1/WT1 expression were identified with significantly different OS. Specific differentially expressed genes between these subgroups provide potential prognostic and therapeutic targets.
    Gynecologic Oncology 12/2013; 132(2). DOI:10.1016/j.ygyno.2013.12.021 · 3.69 Impact Factor
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    ABSTRACT: To elucidate molecular pathways contributing to metastatic cancer progression and poor clinical outcome in serous ovarian cancer. Poor survival signatures from three different serous ovarian cancer datasets were compared and a common set of genes was identified. The predictive value of this gene signature was validated in independent datasets. The expression of the signature genes was evaluated in primary, metastatic, and/or recurrent cancers using qPCR and in situ hybridization. Alterations in gene expression by TGFβ1 and functional consequences of loss of COL11A1 were evaluated using pharmacologic and knockdown approaches, respectively. We identified and validated a 10-gene signature (AEBP1, COL11A1, COL5A1, COL6A2, LOX, POSTN, SNAI2, THBS2, TIMP3, VCAN) that is associated with poor overall survival in patients with high-grade serous ovarian cancer. The signature genes encode extracellular matrix proteins involved in collagen remodeling. Expression of the signature genes is regulated by TGFβ1 signaling and is enriched in metastases in comparison to primary ovarian tumors. We demonstrate that levels of COL11A1, one of the signature genes, continuously increase during ovarian cancer disease progression, with the highest expression in recurrent metastases. Knockdown of COL11A1 decreases in vitro cell migration and invasion and tumor progression in mice. Our findings suggest that collagen-remodeling genes regulated by TGFβ1 signaling promote metastasis and contribute to poor overall survival in patients with serous ovarian cancer. Our 10-gene signature has both predictive value and biological relevance and thus may be useful as a therapeutic target.
    Clinical Cancer Research 11/2013; 20(3). DOI:10.1158/1078-0432.CCR-13-1256 · 8.19 Impact Factor

Publication Stats

3k Citations
554.24 Total Impact Points

Institutions

  • 2013–2014
    • University of California, Los Angeles
      • Department of Obstetrics and Gynecology
      Los Ángeles, California, United States
  • 2009–2014
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Ángeles, California, United States
  • 2010–2012
    • Cancer Research Institute
      New York, New York, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2004–2011
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2005–2006
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2002
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States