Integrative Genome Comparison of Primary and Metastatic Melanomas

Roswell Park Cancer Institute, United States of America
PLoS ONE (Impact Factor: 3.23). 05/2010; 5(5):e10770. DOI: 10.1371/journal.pone.0010770
Source: PubMed


A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.

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Available from: Stephan N Wagner, Oct 07, 2015
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    • "We made focus on two proteins which have been involved in cell migration: the centrosomal/Golgi scaffold AKAP350 and the cdc42 effector CIP4. AKAP350 has been identified as a crucial participant in cell migration in different cell contexts, including integrin induced T cell migration, and epithelial and melanoma cell migration in experimental wounds (El Din El Homasany et al., 2005; Rivero et al., 2009; Kabbarah et al., 2010). Previous studies suggested that AKAP350 facilitates directional cell migration by enabling microtubule nucleation at the Golgi apparatus (Rivero et al., 2009), which is necessary for proper trafficking of membrane components towards the leading edge (Efimov et al., 2007). "
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    ABSTRACT: The acquisition of a migratory phenotype is central in processes as diverse as embryo differentiation and tumor metastasis. An early event in this phenomenon is the generation of a nucleus-centrosome-Golgi back to front axis. AKAP350 is a Golgi/centrosome scaffold protein involved in microtubule nucleation. AKAP350 interacts with CIP4, a cdc42 effector that regulates actin dynamics. The present study aimed to characterize the participation of centrosomal AKAP350 in the acquisition of migratory polarity, and the involvement of CIP4 in the pathway. The decrease in total or in centrosomal AKAP350 led to decreased formation of the nucleus-centrosome-Golgi axis and defective cell migration. CIP4 localized at the centrosome. That was enhanced in migratory cells, but inhibited in cells with decreased centrosomal AKAP350. The interference with CIP4 expression or with CIP4/AKAP350 interaction also led to defective cell polarization. Centrosome positioning, but not nuclear movement was affected by loss of CIP4 or AKAP350 function. Our results support a model where AKAP350 recruits CIP4 to the centrosome, providing a centrosomal scaffold to integrate microtubule and actin dynamics, thus enabling centrosome polarization, and ensuring cell migration directionality. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 07/2015; 128(17). DOI:10.1242/jcs.170878 · 5.43 Impact Factor
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    • "It is caused by both genetic defects and environmental factors such as UV exposure [Chin, 2003; Chin et al., 2006; Ghosh and Chin, 2009]. The roles of genetic defects in the carcinogenesis and metastasis have been studied extensively [Kabbarah et al., 2010]. "
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    Journal of Cellular Biochemistry 03/2013; 114(9). DOI:10.1002/jcb.24549 · 3.26 Impact Factor
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    • "Imp3 is expressed predominantly during embryogenesis and in various tumors [7]–[14], with its expression being limited to the placenta and testis in normal adult mice [9]. Imp3 is thus considered an oncofetal protein and is highly expressed in various human malignancies [8], [9], [15], [16]. "
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