Immunomodulatory Synthetic Glycocluster Molecule Prevents Melanoma Growth In Vivo.

Triacedimannose (TADM) is a synthetic trivalent acetylated glycocluster and a transmembrane macrophage activator independent of the mannose receptor. TADM induces Th1-type immune responses and suppresses Th2-type cytokines in acute and chronic allergic inflammation models in vivo. We, therefore, wanted to test whether TADM could also facilitate anti-tumour tissue responses similar to what has been observed for the immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4.

De Novo Multi-Omics Pathway Analysis Designed for Prior Data Independent Inference of Cell Signaling Pathways.

New tools for cell signaling pathway inference from multi-omics data that are independent of previous knowledge are needed. Here, we propose a new de novo method, the de novo multi-omics pathway analysis (DMPA), to model and combine omics data into network modules and pathways. DMPA was validated with published omics data and was found accurate in discovering reported molecular associations in transcriptome, interactome, phosphoproteome, methylome, and metabolomics data, and signaling pathways in multi-omics data.

An Unbiased Functional Genetics Screen Identifies Rare Activating ERBB4 Mutations.

Unlabelled: Despite the relatively high frequency of somatic mutations in various cancer types, only a few activating mutations have been characterized, primarily due to lack of mutational hotspots in the gene. Here, we utilized our previously published pipeline, an screen for activating mutations, to perform an unbiased functional screen to identify potential activating ERBB4 mutations from a randomly mutated expression library. Ten potentially activating mutations were identified and subjected to validation by functional and structural analyses.

Therapeutic Potential of Targeting the SUMO Pathway in Cancer.

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer.

The guanine nucleotide exchange factor VAV3 participates in ERBB4-mediated cancer cell migration.

ERBB4 is a member of the epidermal growth factor receptor (EGFR)/ERBB subfamily of receptor tyrosine kinases that regulates cellular processes including proliferation, migration, and survival. ERBB4 signaling is involved in embryogenesis and homeostasis of healthy adult tissues, but also in human pathologies such as cancer, neurological disorders, and cardiovascular diseases. Here, an MS-based analysis revealed the Vav guanine nucleotide exchange factor 3 (VAV3), an activator of Rho family GTPases, as a critical ERBB4-interacting protein in breast cancer cells.

An unbiased screen for activating epidermal growth factor receptor mutations.

Cancer tissues harbor thousands of mutations, and a given oncogene may be mutated at hundreds of sites, yet only a few of these mutations have been functionally tested. Here, we describe an unbiased platform for the functional characterization of thousands of variants of a single receptor tyrosine kinase (RTK) gene in a single assay. Our een for ctivating utations (iSCREAM) platform enabled rapid analysis of mutations conferring gain-of-function RTK activity promoting clonal growth.

Genome-wide screen of gamma-secretase-mediated intramembrane cleavage of receptor tyrosine kinases.

Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated intramembrane proteolysis, in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is unknown whether they can exploit this new signaling mechanism. Here we used a system-wide screen to address the frequency of susceptibility to gamma-secretase cleavage among human RTKs.