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.

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 αvß3 or αvß5 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.

Plasma membrane proteoglycans syndecan-2 and syndecan-4 engage with EGFR and RON kinase to sustain carcinoma cell cycle progression.

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 α3ß1 and α6ß4 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 SSTNEGFR) disrupts the entire complex and causes a rapid, global arrest of the cell cycle. Normal epithelial cells do not recruit these additional receptors to the adhesion mechanism and are not arrested by SSTNEGFR. Although EGFR docking with Sdc4 in the tumor cells is required, cell cycle progression does not depend on EGFR kinase. Instead, progression depends on RON kinase, activated by its incorporation into the complex. RON activates ABL1, which suppresses p38 mitogen-activated protein kinase and prevents a p38-mediated signal that would otherwise arrest the cell cycle. These findings add to the growing list of receptor tyrosine kinases that support tumorigenesis when activated by their association with syndecans at sites of matrix adhesion and identify new potential targets for cancer therapy.

A novel stilbene-like compound that inhibits melanoma growth by regulating melanocyte differentiation and proliferation.

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.