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

2018 ◽  
Author(s):  
Wolf-Dietrich Heyer ◽  
Ray Monnat ◽  
Petr Cejka
Keyword(s):  
Microsatellite Instability ◽  
Tumor Cells ◽  
Werner Syndrome ◽  
Selective Vulnerability

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 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.

Abstract 2560: 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 ◽  
Werner Syndrome ◽  
Selective Vulnerability

Abstract 2560: 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 ◽  
Werner Syndrome ◽  
Selective Vulnerability

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.

Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability

2018 ◽  
Author(s):  
Lorn Kategaya ◽  
Senthil K. Perumal ◽  
Jeffrey H. Hager ◽  
Lisa D. Belmont
Keyword(s):  
Microsatellite Instability ◽  
Cancer Cells ◽  
Werner Syndrome

scholarly journals PD-L1 Expression Patterns in Microsatellite Instability-High Intestinal Adenocarcinoma Subtypes

2019 ◽  
Vol 152 (3) ◽  
pp. 384-391 ◽  
Author(s):  
Jordan Roberts ◽  
Safia N Salaria ◽  
Justin Cates ◽  
Yang Wang ◽  
Cindy Vnencak-Jones ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Tumor Cells ◽  
Mucinous Adenocarcinoma ◽  
Expression Patterns ◽  
Inflammatory Cells ◽  
Medullary Carcinoma ◽  
Molecular Features ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
Histologic Subtypes

Abstract Objectives To investigate patterns of programmed death protein-1 (PD-L1) expression in microsatellite instability (MSI)-high intestinal carcinomas and correlate them with pathologic and molecular features. Methods One hundred and fifteen MSI-high and 41 microsatellite stable carcinomas were included. Tumor sections were immunohistochemically labeled for PD-L1. The results were correlated with histologic subtypes, MSI, and BRAF status. Results As expected, MSI status was associated with PD-L1 expression. Among 115 MSI-high tumors, PD-L1 expression was observed on tumor cells in 28 tumors and on tumor-associated inflammatory cells in 77 tumors. Medullary carcinoma demonstrated more frequent PD-L1 expression on tumor cells than mucinous and typical adenocarcinoma. PD-L1 expression was more frequent in medullary and typical adenocarcinoma than in mucinous adenocarcinoma based on combined positive scores. Tumors with more nucleotide shifts by PCR-based MSI testing were more likely to express PD-L1. Conclusions Expression of PD-L1 is different among different histologic subtypes of MSI-high intestinal carcinomas.

scholarly journals Evaluation of the Role of Circulating Tumor Cells and Microsatellite Instability Status in Predicting Outcome of Advanced CRC Patients

2020 ◽  
Vol 10 (4) ◽  
pp. 235
Author(s):  
Ippokratis Messaritakis ◽  
Maria Sfakianaki ◽  
Konstantinos Vogiatzoglou ◽  
Asimina Koulouridi ◽  
Chara Koutoulaki ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Microsatellite Instability ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Performance Status ◽  
Metastatic Potential ◽  
Tumor Location ◽  
High Status ◽  
Predicting Outcome

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death due to its high metastatic potential. This study aimed to investigate the detection and heterogeneity of circulating tumor cells (CTCs) and the microsatellite instability (MSI) status in advanced CRC patients prior to any systemic front-line treatment. Peripheral whole blood was obtained from 198 patients. CTCs were detected using double immunofluorescence and a real time-polymerase chain reaction assay; whereas MSI status was evaluated using fragment analysis. Median age of the patients was 66 years, 63.1% were males, 65.2% had a colon/sigmoid tumor location and 90.4% had a good performance status (PS). MSI-High status was detected in 4.9% of the patients; 33.3%, 56.1% and 8.6% patients had at least one detectable CEACAM5+/EpCAM+, CEACAM5+/EpCAM− and CEACAM5−/EpCAM+ CTC, respectively, and 9.1% of the patients had CEACAM5mRNA-positive CTCs. Following multivariate analysis, age, PS and MSI were confirmed as independent prognostic factors for decreased time to progression, whereas age, PS and CTC presence were confirmed as independent prognostic factors for decreased overall survival. In conclusion, our data support the use of CEACAM5 as a dynamic adverse prognostic CTC biomarker in patients with metastatic CRC and MSI-High is considered an unfavorable prognostic factor in metastatic CRC patient tumors.

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