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Previous studies have shown that the type I IGFR (IGF1R) suppresses apoptosis when it is autoactivated by coupling its extracellular domain to a matrix adhesion receptor complex consisting of syndecan-1 (Sdc1) and αvβ3 or αvβ5 integrin. We now report that head and neck squamous cell carcinoma (HNSCC) relies on this receptor complex. Disruption of the complex in HNSCC cells in vitro with a peptide mimetic of the organizer site in Sdc1 (called SSTNIGF1R) inactivates IGF1R, even in the presence of IGF1, and relieves the suppression of apoptosis signal-regulating kinase-1 (ASK1), dramatically reducing tumor cell survival. Normal epithelial cells do not assemble this receptor complex, require IGF1 to activate the IGF1R, and are refractory to SSTNIGF1R. In vivo, SSTNIGF1R reduced the growth of patient-derived HNSCC tumors in immunodeficient mice by 85%–95%. IGF1R's assimilation into the matrix receptor complex, which is detected in these tumors using the proximity ligation assay (PLA), is quantitatively disrupted by SSTNIGF1R, coinciding with ASK1 activation. PLA also detects the IGF1R-containing receptor complex in the archival sections of tonsil carcinomas, whereas the adjacent benign epithelium is negative. Likewise, PLA screening of oropharyngeal and adenoid cystic tumor microarrays demonstrated that over 95% of the tumors contained this unique receptor complex with no detectable expression in benign tissue. These findings suggest that HNSCC upregulates and is highly dependent on IGF1R signaling via this adhesion receptor complex. Targeting this mechanism with novel therapeutics, including highly specific SSTNIGF1R, is likely to offer promising outcomes for patients with carcinoma. Significance: A newly developed biomarker reveals upregulation of an antiapoptotic IGF1R-integrin-syndecan receptor complex in head and neck cancer and documents disruption of the complex in patient-derived tumor xenografts (PDX) treated with the inhibitor SSTNIGF1R. A corresponding blockade in PDX growth in the presence of this inhibitor demonstrates that therapies designed to target this mechanism will likely offer promising outcomes for patients with head and neck cancer.

Epidermal growth factor receptor (EGFR) is a causal factor in carcinoma, yet many carcinoma patients are resistant to EGFR inhibitors. Potential insight into this resistance stems from prior work that showed EGFR in normal epithelial cells docks to the extracellular domain of the plasma membrane proteoglycan syndecan-4 (Sdc4) engaged with α3β1 and α6β4 integrins. We now report that this receptor complex is modified by the recruitment of syndecan-2 (Sdc2), the Recepteur d'Origine Nantais (RON) tyrosine kinase, and the cellular signaling mediator Abelson murine leukemia viral oncogene homolog 1 (ABL1) in triple-negative breast carcinoma and head and neck squamous cell carcinoma, where it contributes to EGFR kinase-independent proliferation. Treatment with a peptide mimetic of the EGFR docking site in the extracellular domain of Sdc4 (called SSTN

Cosmetic practices that use skin-lightening agents to obtain desired skin tones or treat pigment abnormalities have been popular worldwide. However, the molecular and cellular mechanisms of these agents are still largely unknown. Here we identified a family of compounds, with the lead compound named A11, that exhibited strong pigment reduction in developing zebrafish embryos. The pigment inhibition lasted for several days and is effective both before and after melanogenesis. By comparison with several known skin-lightening compounds, A11 appeared to be more potent and caused slower pigment recovery after withdrawal. A11, however, did not inhibit tyrosinase or cause apoptosis in melanocytes. We further found that A11 suppressed proliferation in melanocytes and reduced the number of differentiated melanocytes by activating MAPK (mitogen-activated protein kinase) and Akt. Finally, A11 also caused melanin reduction in mammalian melanocytes. Together, A11 might be a potent skin-lightening agent with novel mechanisms.

Melanoma is the most aggressive form of skin cancer. Current challenges to melanoma therapy include the adverse effects from immunobiologics, resistance to drugs targeting the MAPK pathway, intricate interaction of many signal pathways, and cancer heterogeneity. Thus combinational therapy with drugs targeting multiple signaling pathways becomes a new promising therapy. Here, we report a family of stilbene-like compounds called A11 that can inhibit melanoma growth in both melanoma-forming zebrafish embryos and mouse melanoma cells. The growth inhibition by A11 is a result of mitosis reduction but not apoptosis enhancement. Meanwhile, A11 activates both MAPK and Akt signaling pathways. Many A11-treated mouse melanoma cells exhibit morphological changes and resemble normal melanocytes. Furthermore, we found that A11 causes down-regulation of melanocyte differentiation genes, including Pax3 and MITF. Together, our results suggest that A11 could be a new melanoma therapeutic agent by inhibiting melanocyte differentiation and proliferation.

The vast bacteriophage population harbors an immense reservoir of genetic information. Almost 2000 phage genomes have been sequenced from phages infecting hosts in the phylum Actinobacteria, and analysis of these genomes reveals substantial diversity, pervasive mosaicism, and novel mechanisms for phage replication and lysogeny. Here, we describe the isolation and genomic characterization of 46 phages from environmental samples at various geographic locations in the U.S. infecting a single Arthrobacter sp. strain. These phages include representatives of all three virion morphologies, and Jasmine is the first sequenced podovirus of an actinobacterial host. The phages also span considerable sequence diversity, and can be grouped into 10 clusters according to their nucleotide diversity, and two singletons each with no close relatives. However, the clusters/singletons appear to be genomically well separated from each other, and relatively few genes are shared between clusters. Genome size varies from among the smallest of siphoviral phages (15,319 bp) to over 70 kbp, and G+C contents range from 45-68%, compared to 63.4% for the host genome. Although temperate phages are common among other actinobacterial hosts, these Arthrobacter phages are primarily lytic, and only the singleton Galaxy is likely temperate.