RRM2 Is a CTNNB1 Transport Regulator Promoting Colon Cancer Progression.

Background/aim: The cytoplasmic retention and stabilization of CTNNB1 (β-catenin) in response to Wnt is well documented in playing a role in tumor growth. Here, through the utilization of a multiplex siRNA library screening strategy, we investigated the modulation of CTNNB1 function in tumor cell progression by ribonucleoside-diphosphate reductase subunit M2 (RRM2).

Materials And Methods: We conducted a multiplex siRNA screening assay to identify targets involved in CTNNB1 nuclear translocation.

Current advances in comprehensive omics data mining for oncology and cancer research.

The availability of a large amount of multiomics data enables data-driven discovery studies on cancers. High-throughput data on mutations, gene/protein expression, immune scores (tumor-infiltrating cells), drug screening, and RNAi (shRNAs and CRISPRs) screening are major integrated components of patient samples and cell line datasets. Improvements in data access and user interfaces make it easy for general scientists to carry out their data mining practices on integrated multiomics data platforms without computational expertise.

Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells.

We investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cancer stem cell (CSC)-enriched cultures and bulk/general mixed cell cultures (BCCs) with RNAi were employed to determine the effect of loss in cancer cell lines from the ovary, breast, stomach, lung, colon and brain.

Screening of the siGPCR library in combination with cisplatin against lung cancers.

The screening of siRNAs targeting 390 human G protein-coupled receptors (GPCRs) was multiplexed in combination with cisplatin against lung cancer cells. While the cell viability measure hardly captured the anticancer effect of siGPCRs, the direct cell count revealed the anticancer potential of diverse GPCRs (46 hits with > twofold growth inhibition, p-value < 0.01).

MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer.

Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism.

ARL2 is required for homologous recombination repair and colon cancer stem cell survival.

ARL2 regulates the dynamics of cytological components and is highly expressed in colon cancer tissues. Here, we report novel roles of ARL2 in the cell nucleus and colon cancer stem cells (CSCs). ARL2 is expressed at relatively low levels in K-RAS active colon cancer cells, but its expression is induced in CSCs.

Q-omics: Smart Software for Assisting Oncology and Cancer Research.

The rapid increase in collateral omics and phenotypic data has enabled data-driven studies for the fast discovery of cancer targets and biomarkers. Thus, it is necessary to develop convenient tools for general oncologists and cancer scientists to carry out customized data mining without computational expertise. For this purpose, we developed innovative software that enables user-driven analyses assisted by knowledge-based smart systems.

Targeting a Lipid Desaturation Enzyme, SCD1, Selectively Eliminates Colon Cancer Stem Cells through the Suppression of Wnt and NOTCH Signaling.

The elimination of the cancer stem cell (CSC) population may be required to achieve better outcomes of cancer therapy. We evaluated stearoyl-CoA desaturase 1 (SCD1) as a novel target for CSC-selective elimination in colon cancer. CSCs expressed more SCD1 than bulk cultured cells (BCCs), and blocking SCD1 expression or function revealed an essential role for SCD1 in the survival of CSCs, but not BCCs.

MicroRNA 34a-AXL Axis Regulates Vasculogenic Mimicry Formation in Breast Cancer Cells.

Targeting the tumor vasculature is an attractive strategy for cancer treatment. However, the tumor vasculature is heterogeneous, and the mechanisms involved in the neovascularization of tumors are highly complex. Vasculogenic mimicry (VM) refers to the formation of vessel-like structures by tumor cells, which can contribute to tumor neovascularization, and is closely related to metastasis and a poor prognosis.

Analysis of Cross-Association between mRNA Expression and RNAi Efficacy for Predictive Target Discovery in Colon Cancers.

The availability of large-scale, collateral mRNA expression and RNAi data from diverse cancer cell types provides useful resources for the discovery of anticancer targets for which inhibitory efficacy can be predicted from gene expression. Here, we calculated bidirectional cross-association scores (predictivity and descriptivity) for each of approximately 18,000 genes identified from mRNA and RNAi (i.e.

Overexpression and Selective Anticancer Efficacy of in Mutant Lung Cancers.

Oncogenic gain-of-function mutations are clinical biomarkers for most targeted therapies, as well as represent direct targets for drug treatment. Although loss-of-function mutations involving the tumor suppressor gene, are important in lung cancer progression, is not the direct target for anticancer agents. We attempted to identify cancer transcriptome signatures associated with loss-offunction mutations.

Dissecting phenotypic responses of the druggable targetome in cancers.

Although a large amount of screening data comprising target genes and/or drugs tested against cancer cell line panels are available, different assay conditions and readouts limit the integrated analysis and batch-to-batch comparison of these data. Here, we systematically produced and analyzed the anticancer effect of the druggable targetome to understand the varied phenotypic outcomes of diverse functional classes of target genes. A library of siRNAs targeting ~4,800 druggable genes was screened against cancer cell lines under 2D and/or 3D assay conditions.

β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer.

The availability of large-scale drug screening data on cell line panels provides a unique opportunity to identify predictive biomarkers for targeted drug efficacy. Analysis of diverse drug data on ~990 cancer cell lines revealed enhanced sensitivity of insulin-like growth factor 1 receptor/ Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) in colon cancer cells. Interestingly, β-catenin/TCF(T cell factor)-responsive promoter activity exhibited a significant positive association with IGF-1R/IR TKI response, while the mutational status of direct upstream genes, such as CTNNB1 and APC, was not significantly associated with the response.

QSurface: fast identification of surface expression markers in cancers.

Background: Cell surface proteins have provided useful targets and biomarkers for advanced cancer therapies. The recent clinical success of antibody-drug conjugates (ADCs) highlights the importance of finding selective surface antigens for given cancer subtypes. We thus attempted to develop stand-alone software for the analysis of the cell surface transcriptome of patient cancer samples and to prioritize lineage- and/or mutation-specific over-expression markers in cancer cells.

Transcriptome modeling and phenotypic assays for cancer precision medicine.

Cancer precision medicine requires clinically actionable biomarkers for patient stratification and a better prediction of clinical outcome. Although thousands of cancer-enriched mutated genes have been reported by global sequencing projects, to date, only a few oncogenic mutations have been confirmed as effective biomarkers in cancer therapies. The low frequency and varied profile (i.

Patient sample-oriented analysis of gene expression highlights extracellular signatures in breast cancer progression.

Although a large collection of cancer cell lines are useful surrogates for patient samples, the physiological relevance of observed molecular phenotypes in cell lines remains controversial. Because transcriptome data are a representative set of molecular phenotypes in cancers, we systematically analyzed the discrepancy of global gene expression profiles between patient samples and cell lines in breast cancers. While the majority of genes exhibited general consistency between patient samples and cell lines, the expression of genes in the categories of extracellular matrix, collagen trimers, receptor activity, catalytic activity and transporter activity were significantly up-regulated only in tissue samples.

Loss-of-function screens of druggable targetome against cancer stem-like cells.

Cancer stem-like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression.

Cardiac glycosides display selective efficacy for STK11 mutant lung cancer.

Although STK11 (LKB1) mutation is a major mediator of lung cancer progression, targeted therapy has not been implemented due to STK11 mutations being loss-of-function. Here, we report that targeting the Na(+)/K(+)-ATPase (ATP1A1) is synthetic lethal with STK11 mutations in lung cancer. The cardiac glycosides (CGs) digoxin, digitoxin and ouabain, which directly inhibit ATP1A1 function, exhibited selective anticancer effects on STK11 mutant lung cancer cell lines.

Differential regulation and synthetic lethality of exclusive RB1 and CDKN2A mutations in lung cancer.

Genetic alterations in lung cancer are distinctly represented in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Mutation of the RB1 and CDKN2A genes, which are tightly associated with cell cycle regulation, is exclusive to SCLC and NSCLC cells, respectively. Through the systematic analysis of transcriptome and proteome datasets for 318 cancer cell lines, we characterized differential gene expression and protein regulation in RB1-mutant SCLC and CDKN2A-mutant NSCLC.

Glucose starvation induces mutation and lineage-dependent adaptive responses in a large collection of cancer cell lines.

Tolerance of glucose deprivation is an important factor for cancer proliferation, survival, migration and progression. To systematically understand adaptive responses under glucose starvation in cancers, we analyzed reverse phase protein array (RPPA) data of 115 protein antibodies across a panel of approximately 170 heterogeneous cancer cell lines, cultured under normal and low glucose conditions. In general, glucose starvation broadly altered levels of many of the proteins and phosphoproteins assessed across the cell lines.

Analysis of image-based phenotypic parameters for high throughput gene perturbation assays.

Although image-based phenotypic assays are considered a powerful tool for siRNA library screening, the reproducibility and biological implications of various image-based assays are not well-characterized in a systematic manner. Here, we compared the resolution of high throughput assays of image-based cell count and typical cell viability measures for cancer samples. It was found that the optimal plating density of cells was important to obtain maximal resolution in both types of assays.

MACE: mutation-oriented profiling of chemical response and gene expression in cancers.

Summary: The mutational status of specific cancer lineages can affect the sensitivity to or resistance against cancer drugs. The MACE database provides web-based interactive tools for interpreting large chemical screening and gene expression datasets of cancer cell lines in terms of mutation and lineage categories. GI50 data of chemicals against individual NCI60 cell lines were normalized and organized to statistically identify mutation- or lineage-specific chemical responses.

Integrated analysis of transcriptomes of cancer cell lines and patient samples reveals STK11/LKB1-driven regulation of cAMP phosphodiesterase-4D.

The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes.

Dissecting the global variation of gene expression for the functional interpretation of transcriptome data.

To perform their biological functions, individual genes exhibit varying ranges of expression levels. Thus, considering the intrinsic variability of gene expression can improve geneset-based functional analyses which are typically used to interpret transcriptome data. Through the extensive quantitative analysis of the expressional variability of individual genes using large collections of transcriptome and proteome data, we found the existence of the intrinsic variability of gene expression at the transcriptional level.