Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells
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Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells. / Knappe, Nathalie; Novak, Daniel; Weina, Kasia; Bernhardt, Mathias; Reith, Maike; Larribere, Lionel; Hölzel, Michael; Tüting, Thomas; Gebhardt, Christoffer; Umansky, Viktor; Utikal, Jochen.
in: Stem cells (Dayton, Ohio), Jahrgang 34, Nr. 4, 04.2016, S. 832-46.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells
AU - Knappe, Nathalie
AU - Novak, Daniel
AU - Weina, Kasia
AU - Bernhardt, Mathias
AU - Reith, Maike
AU - Larribere, Lionel
AU - Hölzel, Michael
AU - Tüting, Thomas
AU - Gebhardt, Christoffer
AU - Umansky, Viktor
AU - Utikal, Jochen
N1 - © 2016 AlphaMed Press.
PY - 2016/4
Y1 - 2016/4
N2 - The combination of cancer-focused studies and research related to nuclear reprogramming has gained increasing importance since both processes-reprogramming towards pluripotency and malignant transformation-share essential features. Studies have revealed that incomplete reprogramming of somatic cells leads to malignant transformation indicating that epigenetic regulation associated with iPSC generation can drive cancer development [J Mol Cell Biol 2011;341-350; Cell 2012;151:1617-1632; Cell 2014;156:663-677]. However, so far it is unclear whether incomplete reprogramming also affects cancer cells and their function. In the context of melanoma, dedifferentiation correlates to therapy resistance in mouse studies and has been documented in melanoma patients [Nature 2012;490:412-416; Clin Cancer Res 2014;20:2498-2499]. Therefore, we sought to investigate directed dedifferentiation using incomplete reprogramming of melanoma cells. Using a murine model we investigated the effects of partial reprogramming on the cellular plasticity of melanoma cells. We demonstrate for the first time that induced partial reprogramming results in a reversible phenotype switch in melanoma cells. Partially reprogrammed cells at day 12 after transgene induction display elevated invasive potential in vitro and increased lung colonization in vivo. Additionally, using global gene expression analysis of partially reprogrammed cells, we identified SNAI3 as a novel invasion-related marker in human melanoma. SNAI3 expression correlates with tumor thickness in primary melanomas and thus, may be of prognostic value. In summary, we show that investigating intermediate states during the process of reprogramming melanoma cells can reveal novel insights into the pathogenesis of melanoma progression. We propose that deeper analysis of partially reprogrammed melanoma cells may contribute to identification of yet unknown signaling pathways that can drive melanoma progression.
AB - The combination of cancer-focused studies and research related to nuclear reprogramming has gained increasing importance since both processes-reprogramming towards pluripotency and malignant transformation-share essential features. Studies have revealed that incomplete reprogramming of somatic cells leads to malignant transformation indicating that epigenetic regulation associated with iPSC generation can drive cancer development [J Mol Cell Biol 2011;341-350; Cell 2012;151:1617-1632; Cell 2014;156:663-677]. However, so far it is unclear whether incomplete reprogramming also affects cancer cells and their function. In the context of melanoma, dedifferentiation correlates to therapy resistance in mouse studies and has been documented in melanoma patients [Nature 2012;490:412-416; Clin Cancer Res 2014;20:2498-2499]. Therefore, we sought to investigate directed dedifferentiation using incomplete reprogramming of melanoma cells. Using a murine model we investigated the effects of partial reprogramming on the cellular plasticity of melanoma cells. We demonstrate for the first time that induced partial reprogramming results in a reversible phenotype switch in melanoma cells. Partially reprogrammed cells at day 12 after transgene induction display elevated invasive potential in vitro and increased lung colonization in vivo. Additionally, using global gene expression analysis of partially reprogrammed cells, we identified SNAI3 as a novel invasion-related marker in human melanoma. SNAI3 expression correlates with tumor thickness in primary melanomas and thus, may be of prognostic value. In summary, we show that investigating intermediate states during the process of reprogramming melanoma cells can reveal novel insights into the pathogenesis of melanoma progression. We propose that deeper analysis of partially reprogrammed melanoma cells may contribute to identification of yet unknown signaling pathways that can drive melanoma progression.
KW - Animals
KW - Biomarkers, Tumor
KW - Cell Dedifferentiation
KW - Cellular Reprogramming
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Induced Pluripotent Stem Cells
KW - Melanoma
KW - Mice
KW - Mice, Transgenic
KW - Neoplasm Invasiveness
KW - Neoplasm Proteins
KW - Neoplasms, Experimental
KW - Signal Transduction
KW - Snail Family Transcription Factors
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1002/stem.2284
DO - 10.1002/stem.2284
M3 - SCORING: Journal article
C2 - 26753613
VL - 34
SP - 832
EP - 846
JO - STEM CELLS
JF - STEM CELLS
SN - 1066-5099
IS - 4
ER -
