Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

Tan, Tuan Zea; Miow, Qing Hao; Huang, Ruby Yun‐Ju; Wong, Ming Keong; Ye, Jieru; Lau, Jieying Amelia; Wu, Meng; Hadi, Luqman Hakim Bin Abdul; Soong, Richie; Choolani, Mahesh; Davidson, Ben; Nesland, Jahn M.; Wang, Ling Zhi; Matsumura, Noriomi; Mandai, Masaki; Konishi, Ikuo; Goh, Boon Cher; Chang, Jeffrey T.; Thiery, Jean Paul; Mori, Seiichi

doi:10.1002/emmm.201201823

Cited by 207 publications

(267 citation statements)

References 80 publications

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“…S4A). TGFb gene expression signature (126 genes) and EMT scoring methods (254 genes), described earlier were utilized to compare expression signatures (24)(25)(26). As expected, TGFb-treated samples showed higher enrichment for TGFb signature (0.14 for control vs. 0.84 after TGFb, Ã , P < 0.05), validating the Bioinformatic scoring (Fig.…”

Section: Hmox1 Downregulation In Runx3-inactivated Cellssupporting

confidence: 71%

TGFβ Promotes Genomic Instability after Loss of RUNX3

et al. 2018

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Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFb is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFb also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescenceassociated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFb gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFb-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cellextrinsic TGFb signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability.Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFb expressed in the tumor microenvironment. Cancer Res; 78(1); 88-102. Ó2017 AACR.

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Section: Hmox1 Downregulation In Runx3-inactivated Cellssupporting

confidence: 71%

TGFβ Promotes Genomic Instability after Loss of RUNX3

et al. 2018

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“…Finally, we also compared ScreenBEAM with MAGeCK and HitSelect on two other NGS-based FG screens (Qin et al, 2014;Tan et al, 2013), which had massive individual validations of identified hits. We compared the false discovery rates of validated positive hits scored by the three algorithms.…”

Section: Ngs-based Data: Screenbeam Robustly Outperforms Mageck and Hmentioning

confidence: 99%

ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling

Silva

Califano

2015

Bioinformatics

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Motivation: Functional genomics (FG) screens, using RNAi or CRISPR technology, have become a standard tool for systematic, genome-wide loss-of-function studies for therapeutic target discovery. As in many large-scale assays, however, off-target effects, variable reagents' potency and experimental noise must be accounted for appropriately control for false positives. Indeed, rigorous statistical analysis of high-throughput FG screening data remains challenging, particularly when integrative analyses are used to combine multiple sh/sgRNAs targeting the same gene in the library. Method: We use large RNAi and CRISPR repositories that are publicly available to evaluate a novel meta-analysis approach for FG screens via Bayesian hierarchical modeling, Screening Bayesian Evaluation and Analysis Method (ScreenBEAM). Results: Results from our analysis show that the proposed strategy, which seamlessly combines all available data, robustly outperforms classical algorithms developed for microarray data sets as well as recent approaches designed for next generation sequencing technologies. Remarkably, the ScreenBEAM algorithm works well even when the quality of FG screens is relatively low, which accounts for about 80-95% of the public datasets. Availability and implementation: R package and source code are available at: https://github.com/

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“…1C). OVCAR-5 has characteristics of high-grade serous carcinoma (Anglesio et al 2013, Mitra et al 2015, and SKOV-3 cells are atypical nonserous carcinoma cells with mesenchymal characteristics (Anglesio et al 2013, Tan et al 2013. Further studies are required to confirm whether the co-culture findings are generalisable to other ovarian cancer subtypes.…”

Section: Introductionmentioning

confidence: 98%

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

Ricciardelli

Lokman

Ween

et al. 2016

Endocrine-Related Cancer

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Ovarian cancer has a distinct tendency for metastasising via shedding of cancerous cells into the peritoneal cavity and implanting onto the peritoneum that lines the pelvic organs. Once ovarian cancer cells adhere to the peritoneal cells, they migrate through the peritoneal layer and invade the local organs. Alterations in the extracellular environment are critical for tumour initiation, progression and intra-peritoneal dissemination. To increase our understanding of the molecular mechanisms involved in ovarian cancer metastasis and to identify novel therapeutic targets, we recently studied the interaction of ovarian cancer and peritoneal cells using a proteomic approach. We identified several extracellular matrix (ECM) proteins including, fibronectin, TGFBI, periostin, annexin A2 and PAI-1 that were processed as a result of the ovarian cancerperitoneal cell interaction. This review focuses on the functional role of these proteins in ovarian cancer metastasis. Our findings together with published literature support the notion that ECM processing via the plasminogen-plasmin pathway promotes the colonisation and attachment of ovarian cancer cells to the peritoneum and actively contributes to the early steps of ovarian cancer metastasis.

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Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

Cited by 207 publications

References 80 publications

TGFβ Promotes Genomic Instability after Loss of RUNX3

TGFβ Promotes Genomic Instability after Loss of RUNX3

ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling

WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

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