Epithelial ovarian cancer (EOC) has a unique mode of metastasis, where cells shed from the primary tumour, form aggregates called spheroids to evade anoikis, spread through the peritoneal cavity, and adhere to secondary sites. We previously showed that the master kinase Liver kinase B1 (LKB1) is required for EOC spheroid viability and metastasis. We have identified novel (nua) kinase 1 (NUAK1) as a top candidate LKB1 substrate in EOC cells and spheroids using a multiplex inhibitor beads-mass spectrometry approach. We confirmed that LKB1 maintains NUAK1 phosphorylation and promotes its stabilization. We next investigated NUAK1 function in EOC cells. Ectopic NUAK1-overexpressing EOC cell lines had increased adhesion, whereas the reverse was seen in OVCAR8-NUAK1KO cells. In fact, cells with NUAK1 loss generate spheroids with reduced integrity, leading to increased cell death after long-term culture. Following transcriptome analysis, we identified reduced enrichment for cell interaction gene expression pathways in OVCAR8-NUAK1KO spheroids. In fact, the FN1 gene, encoding fibronectin, exhibited a 745-fold decreased expression in NUAK1KO spheroids. Fibronectin expression was induced during native spheroid formation, yet this was completely lost in NUAK1KO spheroids. Co-incubation with soluble fibronectin restored the compact spheroid phenotype to OVCAR8-NUAK1KO cells. In a xenograft model of intraperitoneal metastasis, NUAK1 loss extended survival and reduced fibronectin expression in tumours. Thus, we have identified a new mechanism controlling EOC metastasis, through which LKB1-NUAK1 activity promotes spheroid formation and secondary tumours via fibronectin production.
Ovarian cancer (OC) is the most deadly gynaecological malignancy with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, using cell lines and xenograft models, we demonstrated that relaxin and its associated G-protein coupled receptor RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation and viability. We determined that relaxin signaling activated expression of pro-oncogenic pathways including RHO, MAPK, Wnt and Notch. We found that relaxin is detectable in patient derived OC tumors, ascites and serum. Further, inflammatory cytokines IL-6 and TNF-α activated transcription of relaxin via recruitment of STAT3 and NFκB to the proximal promoter initiating an autocrine feedback loop that potentiated expression. Inhibition of RXFP1 or relaxin increased cisplatin sensitivity of OC cell lines and abrogated in vivo tumor formation. Finally, we demonstrated that a relaxin neutralizing antibody reduced OC cell viability and sensitized cells to cisplatin. Collectively, these data identified the relaxin-RXFP1 autocrine loop as a therapeutic vulnerability in OC.
Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data.
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BackgroundThe dynamic changes that occur in protein expression after treatment of a cancer in vivo are poorly described. In this study we measure the effect of chemotherapy over time on the expression of a panel of proteins in ovarian cancer xenograft models. The objective was to identify phosphoprotein and other protein changes indicative of pathway activation that might link with drug response.MethodsTwo xenograft models, platinum-responsive OV1002 and platinum-unresponsive HOX424, were used. Treatments were carboplatin and carboplatin-paclitaxel. Expression of 49 proteins over 14 days post treatment was measured by quantitative immunofluorescence and analysed by AQUA.ResultsCarboplatin treatment in the platinum-sensitive OV1002 model triggered up-regulation of cell cycle, mTOR and DDR pathways, while at late time points WNT, invasion, EMT and MAPK pathways were modulated. Estrogen receptor-alpha (ESR1) and ERBB pathways were down-regulated early, within 24 h from treatment administration. Combined carboplatin-paclitaxel treatment triggered a more extensive response in the OV1002 model modulating expression of 23 of 49 proteins. Therefore the cell cycle and DDR pathways showed similar or more pronounced changes than with carboplatin alone. In addition to expression of pS6 and pERK increasing, components of the AKT pathway were modulated with pAKT increasing while its regulator PTEN was down-regulated early. WNT signaling, EMT and invasion markers were modulated at later time points. Additional pathways were also observed with the NFκB and JAK/STAT pathways being up-regulated. ESR1 was down-regulated as was HER4, while further protein members of the ERBB pathway were upregulated late. By contrast, in the carboplatin-unresponsive HOX 424 xenograft, carboplatin only modulated expression of MLH1 while carboplatin-paclitaxel treatment modulated ESR1 and pMET.ConclusionsThirteen proteins were modulated by carboplatin and a more robust set of changes by carboplatin-paclitaxel. Early changes included DDR and cell cycle regulatory proteins associating with tumor volume changes, as expected. Changes in ESR1 and ERBB signaling were also observed. Late changes included components of MAPK signaling, EMT and invasion markers and coincided in time with reversal in tumor volume reduction. These results suggest potential therapeutic roles for inhibitors of such pathways that may prolong chemotherapeutic effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2212-6) contains supplementary material, which is available to authorized users.
This paper discusses the use of a cooperative multiple robot system as applied to distributed tracking and sampling of a boundary edge. Within this system the boundary edge is partitioned into subsegments, each allocated to a particular robot such that workload is balanced across the robots. Also, to minimize the time between sampling local areas of the boundary edge, it may be desirable to minimize the difference between each robots progression (i.e. phase) along its allocated sub segment of the edge. The paper introduces a new distributed controller that handles both workload and phase balancing. Simulation results are used to illustrate the effectiveness of the controller in an Autonomous Underwater Vehicle (AUV) under ice edge sampling application. Successful results from experimentation with three iRobot Creates are also presented. I. INTRODUCTION Robots are increasingly being used to perform a large variety of tasks. Commercial applications give robots the ability to assist the disabled, clean homes, and aid in the manufacturing and processing of products. Military applications give robots additional purpose. They can scour fields for mines, search for snipers in urban combat environments, and even maintain full battlefield awareness for soldiers. They also have great potential in scientific exploration. They have the capability to withstand harsh and unforgiving environments thereby giving them the ability to perform tasks humans cannot perform. In single robot systems, there is a higher likelihood of mission failure. If the single robot fails, the mission fails. Further, a single robot can only cover so much area in a given time frame. Multi-robot systems typically do not suffer from such possibility of a single point failure. Multi-robot systems also allow for accomplishing tasks of larger size and complexity when compared with single robot systems. This paper concerns the task of tracking and sampling the (possibly dynamic) boundary of some entity with multiple robots. This is useful for scientific, military, and even commercial applications. For example, boundary tracking can be used to track a crowd of people, survey an oil spill, or detect the edge of a harmful algae bloom with Autonomous Underwater Vehicles (AUVs).
The degree of genetic aberrations characteristic of high-grade serous ovarian cancer (HGSC) makes identification of the molecular features that drive tumor progression difficult. Here, we perform genome-wide RNAi screens and whole-kinome proteomics to identify genes that are critical to their survival. We report that the tetraspanin CD151 contributes to survival of a subset of HGSC cell lines associated with a ZEB transcriptional program and supports the growth of HGSC tumors. Moreover, we show that high CD151 expression is prognostic of poor clinical outcome. We have identified essential kinases that manage biosynthetic stress indicative of the ovarian cancer transformed state. These data suggest that targeting pathways that underlie adaptation to cellular stress states rather than driver oncogenes may provide new therapeutic avenues for treating HGSC. Citation Format: Kyle Francis, Helen Burston, Daphna Mokady, Melany Wagner, Mauricio Medrano, Robert Rottapel. Functional genetic architecture of serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA27.
Purpose: Ovarian cancer frequently relapses due to inherent or acquired resistance to platinum-based therapy. To increase therapeutic response, the checkpoint kinases 1 and 2 (CHK1, CHK2) are being targeted in early clinical trials in combination with DNA damaging agents due to their roles in sensing DNA damage and inducing cell cycle arrest. Due to the limited studies on the use of biomarkers to overcome platinum resistance, we set out to characterize potential targets in a cohort of ovarian tumors and paired platinum sensitivity ovarian cancer cell lines. Methods: Total and phospho-protein expression were measured in a panel of 12 ovarian cancer cell lines using antibody arrays in order to characterize signaling pathways. Differentially expressed proteins were measured in a cohort of 128 pre-treatment malignant ovarian tumour lysates using reverse phase protein arrays. Sulforhodamine B cytotoxicity assays were used to assess the DNA damage response relevance of potential targets in paired platinum-sensitive and -resistant ovarian cancer cell lines. Results: Cell line expression clustering identified two groups that differed in patient history: predominantly platinum-based chemotherapy or chemotherapy-naïve background. The overexpressed proteins in the former cluster comprised mainly DNA damage response proteins including p-CHK1 (Ser317) and p-CHK2 (Ser516) implicating these proteins as potential mediators of platinum resistance. Though p-CHK2 had no prognostic value, high p-CHK1 levels were associated with poor overall survival in univariate analysis (medians 21 vs 38 months; corrected P=0.03). In multivariate analysis using a Cox proportional hazard model with other significant factors from univariate analysis (platinum sensitivity, stage, grade, residual disease, and histology), high p-CHK1 tumors had a relative risk of 3.0 (95% CI 1.1 - 8.0, P=0.03), 5.6 for platinum sensitivity (95% CI 2.8-11.1, P<0.001), 1.9 for tumor stage (95% CI 1.2-3.1, P=0.005), and 1.5 for histology (95% CI 1.1-1.9, P=0.004). CHK1 is phosphorylated at Ser317 during DNA damage and accordingly the DNA damage marker p-H2AX (Ser139) was highly expressed in the high p-CHK1 tumor group (P=0.008). The CHK1/2 inhibitor AZD7762 addition had variable effects on the cisplatin dose response when comparing the platinum-sensitive to the paired platinum-resistant cell lines. 50 nM AZD7762 (5.7% growth inhibition) and cisplatin treatment of the platinum resistant PEO4 cells induced a cisplatin concentration response (combination IC50=1.7μM vs cisplatin IC50=9.8μM) similar to that of its paired platinum sensitive PEO1 cell line (cisplatin IC50=2.7μM). Conclusion: This is the first study to identify p-CHK1 as an independent prognostic ovarian cancer biomarker and supports CHK1 as a therapeutic target in platinum-resistant ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3642. doi:1538-7445.AM2012-3642
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