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Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers.

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, [Tlr9.sup.-/-] autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class [II.sup.+] cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific [Tbet.sup.+], [IFN-[gamma].sup.+], and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient [DO11.sup.gld] T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9., Introduction Cutaneous lupus erythematosus (CLE) refers to dermatologic features of systemic lupus erythematosus (SLE) that may or may not be associated with more systemic manifestations, such as arthritis, nephritis, or [...]

* Context.--One of the major clinical challenges is to predict recurrence of meningioma. Recently, we have found that IMP3, an oncofetal RNA-binding protein, is a biomarker to predict aggressive tumors. Objective.--To investigate whether IMP3 can be used as a new biomarker to predict the recurrence and overall survival of patients with meningiomas. Design.--One hundred seven patients with primary meningiomas were investigated for expression of IMP3 by immunohistochemistry and whether expression of this molecule correlated with tumor recurrence and overall survival. Results.--Tumor recurrence was found in 13 of 107 patients with primary meningioma. Seven of 107 patients (6.5%) with primary meningiomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much higher recurrence rate (P = .004) and a poorer overall survival (P < .001) than did patients with IMP3-negative tumors. The 5-year recurrence-free and overall survival rates were 0% and 36% in IMP3-positive patients versus 89% and 94% in IMP3-negative patients, respectively. Multivariable analysis of IMP3 status (positive versus negative) in primary tumors showed a hazard ratio of 17.89 for recurrence (P = .01), which was much higher than hazard ratios associated with all other known risk factors including higher tumor grades and Ki-67 labeling index. Conclusions.--IMP3 is a potential independent prognostic biomarker that can be used at the time of initial diagnosis of meningioma to identify patients who have a high risk of developing a recurrence., Meningioma is the second most common primary tumor of the central nervous system. It accounts for 13% to 26% of all primary intracranial tumors in adults.1 Meningioma is generally considered [...]

* Context.--Our recent experience with a patient developing cutaneous metastases within 3 months of diagnosis of esophageal adenocarcinoma suggests that altered expression of the cellular adhesion molecules, E-cadherin and CD44v6, may have had a role to play in the rapid onset of metastases. Objective.--To corroborate these findings, we designed a cross-sectional study to investigate the expression of select molecules involved in the metastatic cascade. Design.--E-cadherin, [beta]-catenin, CD44v6, and HER2/neu immunohistochemical stains were performed on archival materials of metastatic adenocarcinoma to the skin from 27 patients and the available corresponding primary tumors in 10 patients. The primary sites included breast (n = 10; 37%), gastrointestinal tract (n = 10; 37%), ovary (n = 1; 4%), thyroid (n = 2; 7%), lung (n = 1; 4%), and unknown primary (n = 3; 11%). Results.--Expression of all markers was noted with the most significant increases observed in [beta]-catenin (26 of 27 cases; 96%), followed by CD44v6 (24 of 27 cases; 89%), E-cadherin (22 of 27 cases; 82%), and HER2/neu (11 of 27 cases; 41%). Contrasting expression of these molecules in the primary versus the metastatic tumors, enhanced expression of CD44v6 was observed in the cutaneous metastases relative to the primary in 6 of 10 (60%) cases. Of interest, 2 of these 6 cases (33%) also showed reduction in E-cadherin--a member of the cadherin family functioning as an invasion suppressor molecule. Conclusions.--These findings reinforce the complexities of the metastatic cascade and imply that the variation in adhesive properties of tumor cells is, perhaps, a consequence of the difference in density of the molecules mediating this process. (Arch Pathol Lab Med. 2009;133:1285-1290), The growing incidence of adenocarcinoma has spurred interest in the identification of molecules or markers that delineate patients at a higher risk of metastases. The weakening of the cell-cell adhesion [...]

Pancreatic adenocarcinoma is a leading cause of cancer-related deaths in the United States. In this study, we studied vascular endothelial growth factor (VEGF) expression in pancreatic adenocarcinoma by immunohistochemical staining. Clinical follow-up and survival data were analyzed. We determined that VEGF was aberrantly overexpressed in a subset of primary pancreatic adenocarcinoma. Statistically, VEGF overexpression was associated with higher stage, higher grade, and lymph node metastasis (P < 0.001, P = 0.012, and P < 0.005, respectively). Additionally, patients of this subset had a much shorter overall survival than patients without VEGF overexpression, as evidenced by Kaplan-Meier plots and the log-rank test (P = 0.001). The 5-year overall survival rate was 17% in patients with VEGF overexpression compared to 52% in patients without VEGF overexpression. The median survival was only 13 months for patients with VEGF overexpression compared to 65 months for patients without. In conclusion, VEGF is a biomarker that identifies a subset of pancreatic ductal adenocarcinoma with aggressive clinical behavior. [ABSTRACT FROM AUTHOR]

Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, including AIM2 . Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3., Competing Interests: Competing interests: JMR is an inventor on patent application #63/478,900 “Diagnosis of skin diseases in veterinary and human patients” for CTCL. JEH & JMR are inventors on patent application #62489191, “Diagnosis and Treatment of Vitiligo” which covers targeting IL-15 and Trm for the treatment of vitiligo; and on patent application #15/851,651, “Anti-human CXCR3 antibodies for the Treatment of Vitiligo” which covers targeting CXCR3 for the treatment of vitiligo. JEH holds equity in Rheos Medicines and TeVido BioDevices; is a founder with equity of Villaris Therapeutics, Aldena Therapeutics, NIRA Biosciences, Vimela Therapeutics, and Klirna Therapeutics; has served as a consultant for Pfizer, Sanofi Genzyme, Incyte, Sun Pharmaceuticals, LEO Pharma, Dermavant, Temprian Therapeutics, AbbVie, Janssen, Almirall, Methuselah Health, Pandion, AnaptysBio, Avita, Aclaris Therapeutics, The Expert Institute, BiologicsMD, Boston Pharma, Sonoma Biotherapeutics, Two Biotech, Admirx, Frazier Management, 3rd Rock Ventrures, Gogen Therapeutics, Granular Therapeutics, Platelet Biogenesis, BridgeBio, Merck, Matchpoint Therapeutics, and Klirna; has served as an investigator for Pfizer, Sanofi Genzyme, Incyte, Sun Pharmaceuticals, LEO Pharma, Dermavant, Aclaris Therapeutics, GSK, Celgene, Dermira, and EMD Serono. LZ, ML & YL are employees of NanoString Technologies. MR is principal or co-investigator of studies sponsored by Pfizer, Biogen, AbbVie, Incyte, LEO Pharma, Abeona Therapeutics, Dermavant, and Target RWE; and MR provides consulting for Pfizer, Biogen, Incyte, Takeda, Inzen, ROME Therapeutics, Almirall, Medicxi, Related Sciences, and VisualDx. Remaining authors declare that they have no competing interests.