scholarly journals Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

2019 ◽  
Author(s):  
Simone Lieb ◽  
Silvia Blaha-Ostermann ◽  
Elisabeth Kamper ◽  
Katharina Ehrenhöfer-Wölfer ◽  
Andreas Schlattl ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Large Scale ◽  
Werner Syndrome ◽  
Cancer Cell Lines ◽  
Selective Vulnerability ◽  
Functional Screening ◽  
Wrn Helicase

AbstractTargeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent large-scale genomic profiling and functional screening of cancer cell lines we identified Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair is frequently detected in human malignancies, in particular in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in the emergence of chromosome breaks, chromatin bridges and micronuclei highlighting defective genome integrity. WRN variants harboring mutations abrogating the ATPase function of WRN helicase fail to rescue the viability phenotype of WRN-depleted MSI-H colorectal cells. Our study suggests that pharmacological inhibition of WRN helicase function might represent a novel opportunity to develop a targeted therapy for MSI-H cancers.

scholarly journals Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Simone Lieb ◽  
Silvia Blaha-Ostermann ◽  
Elisabeth Kamper ◽  
Janine Rippka ◽  
Cornelia Schwarz ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Werner Syndrome ◽  
Cancer Cell Lines ◽  
Selective Vulnerability ◽  
Functional Screening ◽  
Wrn Helicase

Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in severe genome integrity defects. ATP-binding deficient variants of WRN fail to rescue the viability phenotype of WRN-depleted MSI-H cancer cells. Reconstitution and depletion studies indicate that WRN dependence is not attributable to acute loss of MMR gene function but might arise during sustained MMR-deficiency. Our study suggests that pharmacological inhibition of WRN helicase function represents an opportunity to develop a novel targeted therapy for MSI-H cancers.

scholarly journals Productive Infection of Human Breast Cancer Cell Lines with Human Cytomegalovirus (HCMV)

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 641
Author(s):  
Kaitlin M. Branch ◽  
Erica C. Garcia ◽  
Yin Maggie Chen ◽  
Matthew McGregor ◽  
Mikayla Min ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Tumor ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Human Breast ◽  
Breast Tumor Cells

Breast cancer is the leading cause of cancer deaths among women worldwide. There are many known risk factors for breast cancer, but the role of infectious disease remains unclear. Human cytomegalovirus (HCMV) is a widespread herpesvirus that usually causes little disease. Because HCMV has been detected in breast tumor biopsy samples and is frequently transmitted via human breast milk, we investigated HCMV replication in breast tumor cells. Four human breast cancer cell lines with different expression profiles for the key diagnostic markers of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were infected with a bacterial artificial chromosome-derived HCMV clinical strain TB40/E tagged with green fluorescent protein (GFP). Fluorescence microscopy confirmed that all four breast cancer cell lines supported virus entry. RNA was isolated from infected cells and the expression of immediate early (UL123), early (UL54), and late (UL111A) genes was confirmed using PCR. Viral proteins were detected by immunoblotting, and viral progeny were produced during the infection of breast tumor cells, as evidenced by subsequent infection of fibroblasts with culture supernatants. These results demonstrate that breast tumor cells support productive HCMV infection and could indicate that HCMV replication may play a role in breast cancer progression.

scholarly journals Platform-integrated mRNA isoform quantification

2019 ◽  
Vol 36 (8) ◽  
pp. 2466-2473 ◽  
Author(s):  
Jiao Sun ◽  
Jae-Woong Chang ◽  
Teng Zhang ◽  
Jeongsik Yong ◽  
Rui Kuang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Large Scale ◽  
Cancer Cell Lines ◽  
Supplementary Information ◽  
Rna Seq ◽  
Mrna Quantification ◽  
Transcript Quantification ◽  
Isoform Expression ◽  
Isoform Quantification

Abstract Motivation Accurate estimation of transcript isoform abundance is critical for downstream transcriptome analyses and can lead to precise molecular mechanisms for understanding complex human diseases, like cancer. Simplex mRNA Sequencing (RNA-Seq) based isoform quantification approaches are facing the challenges of inherent sampling bias and unidentifiable read origins. A large-scale experiment shows that the consistency between RNA-Seq and other mRNA quantification platforms is relatively low at the isoform level compared to the gene level. In this project, we developed a platform-integrated model for transcript quantification (IntMTQ) to improve the performance of RNA-Seq on isoform expression estimation. IntMTQ, which benefits from the mRNA expressions reported by the other platforms, provides more precise RNA-Seq-based isoform quantification and leads to more accurate molecular signatures for disease phenotype prediction. Results In the experiments to assess the quality of isoform expression estimated by IntMTQ, we designed three tasks for clustering and classification of 46 cancer cell lines with four different mRNA quantification platforms, including newly developed NanoString’s nCounter technology. The results demonstrate that the isoform expressions learned by IntMTQ consistently provide more and better molecular features for downstream analyses compared with five baseline algorithms which consider RNA-Seq data only. An independent RT-qPCR experiment on seven genes in twelve cancer cell lines showed that the IntMTQ improved overall transcript quantification. The platform-integrated algorithms could be applied to large-scale cancer studies, such as The Cancer Genome Atlas (TCGA), with both RNA-Seq and array-based platforms available. Availability and implementation Source code is available at: https://github.com/CompbioLabUcf/IntMTQ. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines

RNA Biology ◽  
2013 ◽  
Vol 10 (2) ◽  
pp. 287-300 ◽  
Author(s):  
Aliaksandr Druz ◽  
Yu-Chi Chen ◽  
Rajarshi Guha ◽  
Michael Betenbaugh ◽  
Scott E. Martin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Large Scale ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Large Scale Screening

scholarly journals Author response: Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

2019 ◽  
Author(s):  
Simone Lieb ◽  
Silvia Blaha-Ostermann ◽  
Elisabeth Kamper ◽  
Janine Rippka ◽  
Cornelia Schwarz ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Tumor Cells ◽  
Werner Syndrome ◽  
Selective Vulnerability ◽  
Author Response

scholarly journals 2371 Validation of a novel PD-L1 assay for bladder cancer circulating tumor cells

2018 ◽  
Vol 2 (S1) ◽  
pp. 36-37
Author(s):  
Nicolas Seranio ◽  
Louise Aguarin ◽  
Jay F. Dorsey ◽  
John P. Christodouleas ◽  
Gary D. Kao
Keyword(s):  
Bladder Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Sampling Error ◽  
Cancer Cell Lines ◽  
Bladder Cancer Patient ◽  
Clinical Practices ◽  
Western Blots

OBJECTIVES/SPECIFIC AIMS: Bladder cancer patients being considered for immune checkpoint blockade are often judged on immunohistochemical staining for the checkpoint target protein PD-L1 in the original surgery or biopsy sample. However, sampling error or the clinical evolution of most patients’ cancer can render the original PD-L1 assessment no longer accurate. In contrast, circulating tumor cells (CTCs) allow serial noninvasive sampling of the current tumor status throughout a patient’s clinical course including those with the highest metastatic potential. We therefore sought to develop a method for quantifying PD-L1 expression in CTCs towards addressing inherent limitations of current UC management. METHODS/STUDY POPULATION: This work utilizes both cancer cell lines as well as patient samples. Positive and negative control cancer cell lines were assessed via “industry standard” antibodies for PD-L1 expression via Western blots and immunofluorescence, and a threshold-based method was developed for reliable quantification. PDL-1 expression was additionally verified via interferon-mediated up-regulation. CTCs isolated from bladder cancer patient samples via a density centrifugation method were then assessed for PD-L1 via the same antibodies. RESULTS/ANTICIPATED RESULTS: We will show preliminary preclinical and clinical data that validates the sensitivity and specificity of our assay. A case study will be presented that illustrate the potential useful of the novel approach we describe and which should be complementary to current clinical practices. In a patient with metastatic bladder cancer, this method effectively detected the PD-L1 expression in CTCs taken at a time coincident to when the patient derived an excellent response to the PD-L1 checkpoint inhibitor Pembrolizumab. DISCUSSION/SIGNIFICANCE OF IMPACT: This work highlights the potential utility of CTCs in the management of bladder cancer. It may be the case that this assay in conjunction with current methods of patient selection for immunotherapy may allow for better response prediction than either method alone.

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