Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.

/pdf/melanoma-exosomes-educate-bone-marrow-progenitor-cells-e1lwduo16o.pdf

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual-level genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses, as there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment.

/pdf/an-atlas-of-genetic-correlations-across-human-diseases-and-11fyqwnh4c.pdf

An atlas of genetic correlations across human diseases and traits.

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

/pdf/partitioning-heritability-by-functional-annotation-using-13dk84e4b8.pdf

Partitioning heritability by functional annotation using genome-wide association summary statistics.

Many studies have demonstrated that the accumulation of aggregate-prone proteins due to defects in cellular quality control systems contributes to the development of neurodegenerative diseases. One form of quality control within neurons is autophagy, an intracellular pathway involved in the breakdown of cytosolic constituents. Lysosomes mediate autophagy, and their dysfunction may contribute to perturbations in cellular homeostasis and affect other organelles such as mitochondria. Mitochondrial malfunction may then further perpetuate lysosomal damage and initiate inflammatory responses. Therefore, lysosomes and mitochondria share a reciprocal relationship where dysfunction in one often affects the function of the other. These consequences of lysosome and mitochondrial impairment complete a deleterious feedback loop that concludes not only in neurodegeneration but also neuroinflammation. Herein, we discuss the primary types of autophagy and their underlying mechanisms, the regulation of lysosomal biogenesis and function, and the link between lysosomal and mitochondrial dysfunction. We conclude this chapter by assessing the role of lysosomal dysfunction in neurodegenerative diseases.

The Deleterious Duo of Neurodegeneration: Lysosomes and Mitochondria

11th Meeting of the European Society for Pigment Cell Research 17-20 September 2003 Aula of Ghent University Voldersstraat 9, Gent, Belgium

siRNA ISOLADO, COMPREENDENDO UM FILAMENTO DE ARN SENTIDO E UM FILAMENTO DE ARN ANTI-SENTIDO COMPLEMENTAR QUE FORMAM JUNTOS UM DuPLEX DE ARN, COMPOSIcaO COMPREENDENDO PELO MENOS UM siRNA E UTILIZAcaO DO MESMO. A presente invencao refere-se aos novos siRNA isolados, compreendendo um filamento de ARN sentido e um filamento de ARN anti-sentido complementar que formam juntos um duplex de ARN, caracterizado pelo fato de que o filamento de ARN sentido compreende uma sequencia que possui no maximo um nucleotideo distinto em relacao a um fragmento de 14 a 30 nucleotideos contiguos da sequencia nucleotidica do exon F do gene codificando para a proteina miosina Va, assim como composicoes que compreendem pelo menos um siRNA e a utilizacao de pelo menos esse siRNA como agente cosmetico ou terapeutico para a despigmentacao da pele.

sirna isolado, compreendendo um filamento de arn sentido e um filamento de arn anti-sentido complementar que formam juntos um dúplex de arn, composição compreendendo pelo menos um sirna e utilização do mesmo

Wendy Westbroek

Papers

The Deleterious Duo of Neurodegeneration: Lysosomes and Mitochondria

11th Meeting of the European Society for Pigment Cell Research 17-20 September 2003 Aula of Ghent University Voldersstraat 9, Gent, Belgium

sirna isolado, compreendendo um filamento de arn sentido e um filamento de arn anti-sentido complementar que formam juntos um dúplex de arn, composição compreendendo pelo menos um sirna e utilização do mesmo

e ffect of the Secretory Small G t Pase r ab27B on Breast c ancer Growth, i nvasion, and Metastasis

IPSC-derived dopaminergic neurons from patients with Gaucher disease and Parkinsonism demonstrate the potential of a new glucocerebrosidase chaperone