Proinvasion metastasis drivers in early-stage melanoma are oncogenes.
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ABSTRACT:
SUBMITTER: Scott KL
PROVIDER: S-EPMC3176328 | biostudies-literature | 2011 Jul
REPOSITORIES: biostudies-literature
Publications
Proinvasion metastasis drivers in early-stage melanoma are oncogenes.
Scott Kenneth L KL Nogueira Cristina C Heffernan Timothy P TP van Doorn Remco R Dhakal Sabin S Hanna Jason A JA Min Chengyin C Jaskelioff Mariela M Xiao Yonghong Y Wu Chang-Jiun CJ Cameron Lisa A LA Perry Samuel R SR Zeid Rhamy R Feinberg Tamar T Kim Minjung M Vande Woude George G Granter Scott R SR Bosenberg Marcus M Chu Gerald C GC DePinho Ronald A RA Rimm David L DL Chin Lynda L
Cancer cell 20110701 1
Clinical and genomic evidence suggests that the metastatic potential of a primary tumor may be dictated by prometastatic events that have additional oncogenic capability. To test this "deterministic" hypothesis, we adopted a comparative oncogenomics-guided function-based strategy involving: (1) comparison of global transcriptomes of two genetically engineered mouse models with contrasting metastatic potential, (2) genomic and transcriptomic profiles of human melanoma, (3) functional genetic scre ...[more]
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Project description:Clinical and genomic evidence support the view that the metastatic potential of a primary tumor may be dictated by transforming events acquired early in the tumorigenic process. It has been proposed that the presence of such pro-metastatic events in early-stage tumors reflects their additional capability to function as oncogenes. Here, to test this ‘deterministic’ hypothesis and identify potential pro-metastasis oncogenes, we adopted a comparative oncogenomics-guided functional genetic screening strategy involving (i) global transcriptomic data from two genetically engineered mouse models of melanoma with contrasting metastatic potential, (ii) genomic and transcriptomic profiles of human primary and metastatic melanoma and (iii) an invasion screen in TERT-immortalized human melanocytes and melanoma cells in vitro as well as (iv) evidence of expression selection in human melanoma tissues. This integrated effort led to the identification of 6 genes that are both potently pro-invasive and oncogenic. Further, we show that one such pro-invasion oncogene, ACP5, can confer spontaneous metastasis in vivo, engages a key pathway governing metastasis and is prognostic in human primary melanomas. The tetracycline-inducible MET-driven mouse (iMet) model (Tyr-rtTA;Tet-Met;Ink4a/Arf-/-) was constructed similar to the previously described iHRAS* model (Tyr-rtTA;Tet-HRASV12G;Ink4a/Arf-/-). RNA from cutaneous melanomas derived from iMet (n=6) or iHRAS* (n=6) models were profiled on Affymetrix M430A_2 chips and resultant transcriptomes were compared to generate a phenotype-based (metastatic capable or not) differentially expressed gene list. Cross-species triangulation to human gene expression and copy number aberrations was based on ortholog mapping.
2011-07-11 | E-GEOD-29074 | biostudies-arrayexpress
Project description:Clinical and genomic evidence support the view that the metastatic potential of a primary tumor may be dictated by transforming events acquired early in the tumorigenic process. It has been proposed that the presence of such pro-metastatic events in early-stage tumors reflects their additional capability to function as oncogenes. Here, to test this ‘deterministic’ hypothesis and identify potential pro-metastasis oncogenes, we adopted a comparative oncogenomics-guided functional genetic screening strategy involving (i) global transcriptomic data from two genetically engineered mouse models of melanoma with contrasting metastatic potential, (ii) genomic and transcriptomic profiles of human primary and metastatic melanoma and (iii) an invasion screen in TERT-immortalized human melanocytes and melanoma cells in vitro as well as (iv) evidence of expression selection in human melanoma tissues. This integrated effort led to the identification of 6 genes that are both potently pro-invasive and oncogenic. Further, we show that one such pro-invasion oncogene, ACP5, can confer spontaneous metastasis in vivo, engages a key pathway governing metastasis and is prognostic in human primary melanomas.
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Project description:Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients.
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