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Neuron-astrocyte communication plays a key role in pathophysiology, however systematic approaches to unveil it are limited. Here, the authors propose SEARCHIN, a multi-modal integrated workflow, as a tool to identify cross-compartment ligand-receptor interactions, applied to ALS models.

Despite the importance of pharmacological and functional genomic screens the readouts are of low complexity. Here the authors introduce PLATE-Seq, a low-cost genome-wide mRNA profiling method to complement high-throughput screening.

VIPER has been successfully used to assess the regulatory activities of proteins from gene expression data, but its dependence on tissue-specific molecular profiles limits its applicability. MetaVIPER, introduced here, enables inference of the protein activities in orphan tissues and single cells.

Aberrant signalling pathway activity is relevant for tumour growth and resistance to therapy, but remains hard to understand and target. Here, the authors develop VESPA, a phosphoproteomics-based machine learning algorithm that can elucidate response and adaptation to drug perturbations in cancer signalling pathways.

This study presents OncoTreat, a framework for the prioritization of compounds targeting mechanistic tumor dependencies in individual patients.

The architecture of gene regulatory networks that govern mammalian cells has been poorly understood. Here, Li et al. present a computational systems approach to elucidate the regulatory logic of the gene network for primed state pluripotency.

The identification of master regulator genes that may be manipulatedin vitro to regulate reprogramming has been difficult. Here, the authors use a computational systems approach to identify three genes (FoxA1, Nkx3.1and the androgen receptor) that can reprogramme fibroblasts to prostate tissue.

RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.

Andrea Califano, Mariano Alvarez and colleagues present an approach, VIPER, for inferring protein activity in single cancer samples based on expression of a protein's downstream targets. The authors use VIPER to predict aberrant protein activity independent of mutational status and validate drug sensitivity predictions using in vitro assays.

Genomic and transcriptomic analysis of 393 non-small cell lung cancer patients treated with checkpoint inhibitors identifies molecular features associated with response.

Characterization of the mutational landscape of tumors is important to understanding disease etiology but does not provide mechanistic insight into the functional role of specific mutations. A new study introduces a statistical mechanical framework that draws on biophysical data from SH2 ___domain–phosphoprotein interactions to predict the functional effects of mutations in cancer.

The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.

Tissue chips with matured human heart, liver, bone and skin tissue niches linked by recirculating vascular flow recapitulate interdependent functions of these organs.

Interaction networks for any protein can be generated using a machine learning algorithm.

Resistance to therapy can be driven by intratumoral heterogeneity. Here, the authors show that drug tolerant persistent cell populations emerge during treatment, and these emergent populations arise through epigenetically mediated cell state transitions rather than sub population selection.

A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma, but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network now reveal the transcription factors that activate expression of mesenchymal genes in malignant glioma.

The authors apply reverse engineering of transcriptional networks to identify the main functional drivers of the pro-leukemic transcriptional activity of TLX1 and TLX3, transcription factors usually altered in T-ALL. The network analysis uncovers RUNX1 as a key mediator of the effects of TLX factors and, consistently, mutations in RUNX1 are found in human T-ALL.

A community computational challenge generates algorithms to predict activity of drug combinations.

Identifying KRAS-specific vulnerabilities helps to target KRAS-driven cancer. Here the authors perform RNA interference screens in 3D cultures of primary tumour cells with KRAS activation and p53 loss and identify UHRF1 as a vulnerability of KRAS-mutant lung cancers

Mammalian genomes are scattered with repetitive sequences, but their biology remains largely elusive. Here, the authors show that transcription can initiate from short tandem repetitive sequences, and that genetic variants linked to human diseases are preferentially found at repeats with high transcription initiation level.

Silva and colleagues develop a network-based HDAC6 score which could predict sensitivity to the HDAC6 inhibitor ricolinstat in preclinical models, as well as patients with HR⁺/HER2⁻ breast cancer that received ricolinstat in a phase 1b clinical trial.

The lateral hypothalamus is implicated in drug reward and addiction. Chen and colleagues find that in the lateral hypothalamus of mice, the proteoglycan syndecan-3 negatively regulates cocaine-seeking behaviour by modulating the effects of glial cell line-derived neurotrophic factor.

Orienting cancer drug discovery to the patient requires relating the genetic features of tumors to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.

This Opinion article discusses the recurring regulatory architecture that is both necessary and sufficient to maintain tumour cell state. Considering this architecture provides a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.

The oncogenic activation of TLX transcription factors demarcates a specific molecular subtype of T cell acute lymphoblastic leukemia (T-ALL). This study identifies aneuploidy induction as a molecular mechanism by which TLX1 transforms T cell progenitors and reveals new TLX1 transcriptional targets, including Bcl11b, a crucial factor in T cell progenitor differentiation and survival, and Chek1, a mitotic checkpoint regulator. The findings delineate the role of TLX1 in T-ALL initiation and maintenance.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

Identifying cell intrinsic mechanisms promoting metastasis are necessary to develop new cancer therapeutics. Here they do cross-species computational analysis and identify nuclear receptor binding SET ___domain Protein 2 (NSD2) as a driver of prostate cancer metastasis.

Shen and colleagues find that initiation of prostate tumours by basal or luminal epithelial cells in mice leads to distinct tumour signatures. Interestingly, they find that although oncogenic transformation of basal cells gives rise to tumours with luminal phenotypes, tumours of luminal origins are more aggressive in functional tests and the distinct signature correlated with that of patients with aggressive tumours.

Diffuse large B cell lymphomas can arise from dysregulation of BCL6 expression. Dalla-Favera and colleagues show that the transcription factor MEF2B regulates BCL6 and is commonly associated with the generation of such lymphomas.

HIFα transcription factors are highly expressed in cancer stem cells from glioma; DYRK1 kinases inhibit the protein ID2 to modulate the level of HIF2α and the tumorigenic properties of glioblastoma-associated cancer stem cells.

To elucidate novel molecular mechanisms underlying neurodegeneration in Parkinson's disease, the authors generated mice for cell type-specific profiling of dopaminergic neurons. Regulatory network analysis of translatome libraries from dopaminergic neurons under degenerative stress facilitated the identification of intrinsic upstream regulators that oppose degeneration. This strategy can be generalized to investigate degeneration of other classes of neurons.

Protein–protein interactions, essential for understanding how a cell functions, are predicted using a new method that combines protein structure with other computationally and experimentally derived clues.

Collaborative competitions in which communities of researchers compete to solve challenges may facilitate more rigorous scrutiny of scientific results.

Piccolo and colleagues perform integrated single-cell analyses and identify YAP/TAZ regulation of glioma stem cell differentiation as a core dependency for tumor maintenance.

In this Perspective, attendees of the Herrenhausen Tumour Heterogeneity meeting discuss the challenges in understanding tumour heterogeneity and propose ways forward for overcoming these hurdles.

Modulatory proteins ensure that transcription factors are active when and where they should be. Wang et al. describe an algorithm for identifying modulators from a compendium of gene expression profiles and experimentally validate four diverse modulators of the MYC oncogene in human B cells.

A study from the FANTOM consortium using single-molecule cDNA sequencing of transcription start sites and their usage in human and mouse primary cells, cell lines and tissues reveals insights into the specificity and diversity of transcription patterns across different mammalian cell types.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adulthood. Here, mutations in multiple genes that regulate the NK-κB pathway are shown to be present in DLBCL, with the most commonly affected being the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NK-κB responses.