In a phosphoproteomic study of neuroblastoma cell lines and cell fractions, including endo-somes and detergent-resistant membranes, 1622 phosphorylated proteins were detected, including more than half ofthe receptortyrosine kinases in the human genome.

Neuroblastoma tumors and cell lines thus represent a snapshot of failed differentiation at different stages in the neural crest sympathoa-drenal lineage [2,4,7,8].

To identify patterns in tyrosine phosphorylation in neuroblastoma, we acquired phospho-proteomic data from 21 neuroblastoma cell lines and cell fractions including endosomes and detergent-resistant lipid rafts as previously characterized [32,33].

These data indicate that neuroblastoma cell lines express and phosphorylate a large fraction of the PNCPs in the human genome.

Notably, four different transplanted human neuroblastoma cell lines [LAN6, SK-N-BE(2), SMS-KCN, and SH-SY5Y] migrated to neural crest target sites, incorporated into the developing ganglia, and expressed neuronal markers specific to mature afferents (S4 Fig).

The potential to migrate along the stereotypical neural crest migration pathways, and differentiate into most neural-crest-derived cell types, suggests that many of the RTK signaling pathways that control differentiation and migration were generally functional in these neuroblastoma cell lines .

To identify patterns in tyrosine phosphorylation in neuroblastoma, we analyzed tyrosine phos-phoproteomic data acquired from 21 neuroblastoma cell lines using immunoprecipitation of tyrosine phosphorylated peptides as previously described [41,42].

Four cell lines [SH-SY5Y, LAN-6, SMS-KCN, and SK-N-BE(2)] were selected for further studies because of their different point mutations in ALK, p53 status, RTK expression, morphology, and growth patterns.

These data indicate that stimulation of one RTK affects the phosphorylation state of other RTKs in neuroblastoma cell lines .

Shown are changes of more than twofold from representative experiments where peak intensity was measured for treatment and control conditions in the same experiment with cell lines and treatments indicated on column labels (e.g., “NGF to C” means NGF-treated compared to control).

In contrast, FYN inhibitory phosphorylation (FYN 531) was increased by NGF in two cell lines (Fig 4B).

By using two different glioblastoma cell lines in our analysis, we have found that glioblasto-ma growth through the insulin signaling pathway is tumor specific.

When we conducted the glioblastoma growth reduction analyses of the LN229 and U87 cell lines, there was almost no change in growth observed in the U87 cell lines , while the LN229 showed a reduction in the glioblastoma tumors’ growth.

Glioblastoma cells lines that rely on the insulin signaling pathway for their aggressive growth phenotype will be more affected by drugs that target the insulin signaling pathway.

The glioblastoma growth rates were found for two distinct experiments (U87 and LN229) by fitting the same model and obtaining different initial conditions and growth rates for the two cell lines .

The experiments used the human retinal pigment epithelial (RPE) cell line D407; and it is an assumption of the model that the same relationships hold in glioma cells (these measurements are the only ones we are aware of that measure IGFBP2 as a function of IGFI levels).

The diameter of the glioblastoma for both cell lines U87 and LN229 was then compared to the original pathway before the removal of the reaction.

The growth rate of the glioblastoma tumor, Eq 5, was determined by regression analysis using the data from both our previous experiments on spheroid growth in vitro using the U87 glio-blastoma cell line and LN229 glioblastoma growth in mice [70].

The U87 and LN229 glioblas-toma cell lines were used to compare glioblastoma cell lines which were more dependent on insulin signaling (LN229) and less dependent on insulin signaling (U87) [3].

for the U87 cell line , there was not a significant change in the glioblastoma volume When either the IGFBP2 to HIFloc or the IGFI to HIFloc connection was removed, see SS Fig.

Sensitivity analysis was summarized by calculating the sensitivity indeX (see below) at 40 days for the LN229 cell line in Table 1.

We extensively characterize drug hits in silico, demonstrating that they slow growth significantly in nine lung cancer cell lines from the NCl-60 collection, and identify CALM1 and PLA2G4A as promising drug targets for lung cancer.

Candidate therapeutics inhibit growth in nine NSCLC cell lines

As an independent validation of our results, we used growth inhibition data from the NCI-6O collection [18] to determine whether the drug candidates we identified are better at slowing growth in lung cancer cell lines .

For all our NCI-6O analyses we used the nine lung cancer cell lines in which over 100 Connectivity Map drugs were tested (see Methods).

One such resource, the Connectivity Map (CMap), which is the focus of our analyses, catalogues the transcriptional responses to drug treatment in human cell lines for over a thousand small molecules [3].

They tested one of their drug hits (17-AAG) in vitro and found that it inhibited growth in two lung adenocarcinoma cell lines .

This validation supported our method: drug candidates identified by CMapBatch were significantly more likely to slow growth in nine lung cancer cell lines than other CMap drugs.

This power-law captures the complex, variable processes underlying bacterial invasion while also enabling differentiation of cell lines .

The power-law parameters capture characteristics of the host-bacterium pair interaction and can differentiate host cell lines .

Characteristic power-law parameters describe uptake in different cell lines

To test this hypothesis, we measured the uptake dynamics of our engineered bacteria (E. coli expressing arabinose-inducible invasin) in several mammalian cell lines , grown under the same condition.

Though simple, the power-law description of uptake is robust in describing invasin-mediated bacterial uptake by mammalian cells, and the extracted power-law parameters can be useful in distinguishing pairs of E. coli strains (expressing varying levels of invasion) and mammalian cell lines .

In particular, we treated several cell lines with increasing MOI.

As such, for more extensive analysis of different cell lines , we chose a high MOI for bacterial infection.

Results in Fig 4B reveal that power-law parameters [3 and 1/ KDeff for different cell lines infected with bacteria at 1000 MOI appeared to fall along a single trajectory.

Uptake in all the cell lines we tested, most of which are cancer models, was positively correlated with MOI but the amount of uptake was quite variable.

This cell line differentiates into neurons and glial cells within 72 hours after growth factor removal, which might explain the faster time scale of our model compared to the Lee model.

Consequently our WNT/fi-catenin model is not only in agreement with data published earlier, but conclusions about WNT/fi-catenin signaling drawn from ReNcell VM197 cells do not appear to be cell line specific and, hence, seem generally applicable.

Indeed, earlier studies on the same cell line , provide eXperimental data, that show these dynamics for the early immediate cell response in untreated ReNcell VM197 cells: p-LRP6 was found to be NOT significantly increased during the early time points (0—3 hours), while fi-catenin shows the ascribed transient activation (cf.

Cross validation studies manifest its predictive capability for other cells and cell lines rendering the model a suitable basis for further studies also in the context of embryonic development, developmental disorders and cancers.

In a recent study with the same cell line , we uncovered an endogenous, WNT-independent activation of WNT/fi-catenin signaling through reactive oxygen species (ROS) in response to initiation of differentiation through growth-factor removal [21].

The ReNcell VM197 is a well-characterized cell line , that has been successfully applied in several studies and proven to be a simple and accepted model to investigate different aspects of neural differentiation [5, 8, 30—32].

The major advantage of this cell line is its rapid differentiation.

Our experimental results are retrieved from ReNcell VM 197 cells—a cell line , that is derived from the ventral midbrain of a 10-week-old human fetus and immortalized by retroviral transduction with v-Myc oncogene (ReNeuron Ltd, Guildford, UK).

The ReNcell VM197 cell line was derived from the ventral mesencephalon region of a human fetal brain tissue and is characterized by a rapid differentiation.

This implies that raft disruption serves as effective inhibitor for WNT/fi-catenin signaling in our cell line .

We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line .

We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line .

The activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) in the MCF7 breast cancer cell line exemplifies the impact of such transient or sustained signalling on cell fate [3, 4].

This pattern was less apparent in the MCF7-HRG cell line where the proportion of known IEGs found in an interval exceeded the overall average towards the end of the time course.

We extracted gene regulatory network data from the ENCODE leukemia cell line , K562, and gene and miRNA eXpression datasets for AML from TCGA.

We identified 50,865 TF1-TF2-target triplets with 1824 unique targets using ChIP-seq data (70 TFs) from ENCODE K562 cell line [5] and 821 distTF-TF-target triplets with 113 unique targets, where distTFs were predicted to bind distal regulatory regions [52].

The miRNA-target pairs that we used for human K562 cell line in this paper were the overlapped pairs among widely used public databases for predicting miRNA-target relationships described in [53].