Tales of diversity: Genomic and morphological characteristics of forty-six Arthrobacter phages

This article describes 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

PD-L1-Targeting Nanoparticles for the Treatment of Triple-Negative Breast Cancer: A Preclinical Model

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Common treatments following surgical resection include PD-1-targeting checkpoint inhibitors (pembrolizumab), as 20% of tumors are PD-L1 positive with or without systemic chemotherapy. Over the last several years, our laboratory has developed nano-immune conjugates (NIC) in which hydrophobic chemotherapy drugs like paclitaxel (PTX) and SN38, the active metabolite of irinotecan, are made water soluble by formulating them into albumin-based nanoparticles (nab) that are hydrophobically linked to various IgG1 monoclonal antibodies, creating an antigen-targetable nano-immune conjugate. To date, we have successfully tested PTX containing NICs linked to either VEGF- or CD20-targeted antibodies in two phase I clinical trials against multiple relapsed ovarian/uterine cancer or non-Hodgkin’s lymphoma, respectively. Herein, we describe a novel NIC created with either PTX or SN38 that is coated with anti-PD-L1-targeting antibodies for the treatment of a preclinical model of TNBC. In vitro testing suggests that the chemotherapy drug and antibody retain their toxicity and ligand binding capability in the context of the NIC. Furthermore, both the PTX and SN-38 NIC demonstrate superior anti-tumor efficacy relative to antibody and chemotherapy drugs alone in a PD-L1 + MDA-MB-231 human TNBC xenograft model, which could translate clinically to patients with TNBC

Inhibiting IGF1R-mediated Survival Signaling in Head and Neck Cancer with the Peptidomimetic SSTNIGF1R

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. </jats:sec

MST1R/RON and EGFR in a complex with syndecans sustain carcinoma S-phase progression by preventing p38MAPK activation

ABSTRACTSyndecan-4 (Sdc4) organizes a complex of receptors consisting of its homologue, Sdc2, the receptor tyrosine kinases EGFR and MST1R/RON, and the laminin-binding α3β1 and α6β4 integrins that depends on a docking site within its extracellular domain. A peptide mimetic of the extracellular docking site, synstatin-EGFR (SSTNEGFR), disrupts the receptor complex and prevents the invasion of non-transformed or carcinoma cells that relies on active EGFR. However, the peptide also prevents DNA replication that relies on active MST1R/RON and c-Abl kinase within the complex, resulting in rapid S-phase arrest of head &amp; neck (HN) and breast carcinoma cells. SSTNEGFRdoes not affect DNA replication in non-transformed oral or breast epithelial cells, but it does block their EGF-dependent invasion. Although EGFR is required as a component of the complex, its kinase activity is not required to sustain S-phase progression in the carcinoma cells, perhaps explaining why many HN and breast carcinomas that overexpress EGFR are nonetheless refractory to EGFR inhibitors. The syndecan-organized receptor complex (Sdc:RTK:ITG complex) appears to suppress stress signals that would otherwise disrupt the replisome engaged in DNA synthesis. SSTNEGFR-treatment of carcinoma cells, or normal oral epithelial cells expressing stress-inducing HPV oncogenes, causes rapid activation of the p38 stress MAPK leading to loss of PCNA from the chromatin and cessation of DNA synthesis. This arrest is independent of the common DNA damage response (DDR) known to activate an S-phase checkpoint, revealing a novel arrest mechanism and a novel receptor complex that is activated on tumor cells to suppress stress-induced proliferation arrest.</jats:p

Melanoma-Derived Extracellular Vesicles Induce CD36-Mediated Pre-Metastatic Niche

CD36 expression in both immune and non-immune cells is known to be directly involved in cancer metastasis. Extracellular vesicles (EVs) secreted by malignant melanocytes play a vital role in developing tumor-promoting microenvironments, but it is unclear whether this is mediated through CD36. To understand the role of CD36 in melanoma, we first analyzed the SKCM dataset for clinical prognosis, evaluated the percentage of CD36 in lymphatic fluid-derived EVs (LEVs), and tested whether melanoma-derived EVs increase CD36 expression and induce M2-macrophage-like characteristics. Furthermore, we performed a multiplex immunofluorescence (MxIF) imaging analysis to evaluate the CD36 expression and its colocalization with various other cells in the lymph node (LN) of patients and control subjects. Our findings show that cutaneous melanoma patients have a worse clinical prognosis with high CD36 levels, and a higher percentage of CD36 in total LEVs were found at baseline in melanoma patients compared to control. We also found that monocytic and endothelial cells treated with melanoma EVs expressed more CD36 than untreated cells. Furthermore, melanoma-derived EVs can regulate immunosuppressive macrophage-like characteristics by upregulating CD36. The spatial imaging data show that cells in tumor-involved sentinel LNs exhibit a higher probability of CD36 expression than cells from control LNs, but this was not statistically significant. Conclusively, our findings demonstrated that CD36 plays a vital role in controlling the immunosuppressive microenvironment in the LN, which can promote the formation of a protumorigenic niche