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Human melanoma: transcriptional plasticity, genomic loh and tumor biology

English title Human melanoma: transcriptional plasticity, genomic loh and tumor biology
Applicant Dummer Reinhard
Number 119989
Funding scheme Project funding
Research institution Dermatologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Dermatology
Start/End 01.04.2008 - 31.07.2011
Approved amount 360'000.00
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Keywords (9)

melanoma; microarray; molecular biology; tissue array; transcriptoma; metastatic progression; phenotype switching; chromosomal aberration; prognosis

Lay Summary (English)

Lead
Lay summary
Melanoma is among the most significant cancers affecting Caucasian populations world-wide. Despite decades of effort, no effective therapy has been found for metastatic disease. Clearly, our knowledge of its cellular and molecular nature is not yet sufficient to impact treatment. Therefore the continuation of research aimed at improving our understanding of melanoma biology is critical.Our laboratory has derived a new hypothesis for melanoma disease progression - the phenotype switching model. This model is based on observations of two different melanoma cell phenotypes differentiable by gene expression profiling, proliferative and invasive capacities, susceptibility to cytokine-mediated growth inhibition, and in vivo growth kinetics. We have shown that melanoma cells may switch between phenotypes in vivo using a xenograft model. This model better explains both intra-lesional heterogeneity and metastatic progression than the existing clonal evolution and cancer stem cell models (the latter of which has recently been shown to be untenable for melanoma anyway). Furthermore, the phenotype switching model offers an explanation for persistent targeted therapy failure. This challenging work was published in 2008.Our group also led a study which identified 71 additional transcriptional targets of the microphthalmia-associated transcription factor (Mitf) which is a critical factor in melanoma cell proliferation. Furthermore, in a separate study our group identified Id2 as a factor involved in modulating the susceptibility of cells to TGF-beta-mediated growth inhibition. Id2 functions by suppressing TGF-beta-mediated up-regulation of p15, which would otherwise arrest the cell cycle. These two studies were published in 2008 and 2009, respectively.Importantly, we recently submitted a paper to Cancer Research detailing our studies into melanoma genomic alteration. We discovered that melanomas could be subdivided into two groups, one showing relatively few genomic alterations and the other with frequent genomic changes. We found that patients yielding stage III or IV samples with frequent genomic change had a significantly worse prognosis when compared with patients yielding stage III or IV samples with infrequent genomic change. We also pointed out frequent genomic change usually includes gain of chromosome 6p and that this region includes the IRF4 oncogene we recently identified as being regulated by Mitf.Combined, our studies make significant contributions to both understanding the molecular and cellular underpinnings of melanoma progression and the impact of genomic alterations to patient survival.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status.
Zipser Marie C, Eichhoff Ossia M, Widmer Daniel S, Schlegel Natalie C, Schoenewolf Nicola L, Stuart Darrin, Liu Weihua, Gardner Humphrey, Smith Paul D, Nuciforo Paolo, Dummer Reinhard, Hoek Keith S (2011), A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status., in Pigment cell & melanoma research, 24(2), 326-33.
Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching.
Eichhoff Ossia M, Weeraratna Ashani, Zipser Marie C, Denat Laurence, Widmer Daniel S, Xu Mai, Kriegl Lydia, Kirchner Thomas, Larue Lionel, Dummer Reinhard, Hoek Keith S (2011), Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching., in Pigment cell & melanoma research, 24(4), 631-642.
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.
Johannessen Cory M, Boehm Jesse S, Kim So Young, Thomas Sapana R, Wardwell Leslie, Johnson Laura A, Emery Caroline M, Stransky Nicolas, Cogdill Alexandria P, Barretina Jordi, Caponigro Giordano, Hieronymus Haley, Murray Ryan R, Salehi-Ashtiani Kourosh, Hill David E, Vidal Marc, Zhao Jean J, Yang Xiaoping, Alkan Ozan, Kim Sungjoon, Harris Jennifer L, Wilson Christopher J, Myer Vic E, Finan Peter M, Root David E (2010), COT drives resistance to RAF inhibition through MAP kinase pathway reactivation., in Nature, 468(7326), 968-972.
Integrative analysis of the melanoma transcriptome.
Berger Michael F, Levin Joshua Z, Vijayendran Krishna, Sivachenko Andrey, Adiconis Xian, Maguire Jared, Johnson Laura A, Robinson James, Verhaak Roel G, Sougnez Carrie, Onofrio Robert C, Ziaugra Liuda, Cibulskis Kristian, Laine Elisabeth, Barretina Jordi, Winckler Wendy, Fisher David E, Getz Gad, Meyerson Matthew, Jaffe David B, Gabriel Stacey B, Lander Eric S, Dummer Reinhard, Gnirke Andreas, Nusbaum Chad (2010), Integrative analysis of the melanoma transcriptome., in Genome research, 20(4), 413-427.
Id2 suppression of p15 counters TGF-beta-mediated growth inhibition of melanoma cells.
Schlegel Natalie C, Eichhoff Ossia M, Hemmi Silvio, Werner Sabine, Dummer Reinhard, Hoek Keith S (2009), Id2 suppression of p15 counters TGF-beta-mediated growth inhibition of melanoma cells., in Pigment cell & melanoma research, 22(4), 445-53.
MEK1 mutations confer resistance to MEK and B-RAF inhibition.
Emery Caroline M, Vijayendran Krishna G, Zipser Marie C, Sawyer Allison M, Niu Lili, Kim Jessica J, Hatton Charles, Chopra Rajiv, Oberholzer Patrick A, Karpova Maria B, MacConaill Laura E, Zhang Jianming, Gray Nathanael S, Sellers William R, Dummer Reinhard, Garraway Levi A (2009), MEK1 mutations confer resistance to MEK and B-RAF inhibition., in Proceedings of the National Academy of Sciences of the United States of America, 106(48), 20411-6.
In vivo switching of human melanoma cells between proliferative and invasive states.
Hoek Keith S, Eichhoff Ossia M, Schlegel Natalie C, Döbbeling Udo, Kobert Nikita, Schaerer Leo, Hemmi Silvio, Dummer Reinhard (2008), In vivo switching of human melanoma cells between proliferative and invasive states., in Cancer research, 68(3), 650-656.
Modeling genomic diversity and tumor dependency in malignant melanoma.
Lin William M, Baker Alissa C, Beroukhim Rameen, Winckler Wendy, Feng Whei, Marmion Jennifer M, Laine Elisabeth, Greulich Heidi, Tseng Hsiuyi, Gates Casey, Hodi F Stephen, Dranoff Glenn, Sellers William R, Thomas Roman K, Meyerson Matthew, Golub Todd R, Dummer Reinhard, Herlyn Meenhard, Getz Gad, Garraway Levi A (2008), Modeling genomic diversity and tumor dependency in malignant melanoma., in Cancer research, 68(3), 664-73.
Novel MITF targets identified using a two-step DNA microarray strategy.
Hoek Keith S, Schlegel Natalie C, Eichhoff Ossia M, Widmer Daniel S, Praetorius Christian, Einarsson Steingrimur O, Valgeirsdottir Sigridur, Bergsteinsdottir Kristin, Schepsky Alexander, Dummer Reinhard, Steingrimsson Eirikur (2008), Novel MITF targets identified using a two-step DNA microarray strategy., in Pigment cell & melanoma research, 21(6), 665-76.

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