TY  - JOUR
A1  - Grimm, Johannes
A1  - Hufnagel, Anita
A1  - Wobser, Marion
A1  - Borst, Andreas
A1  - Haferkamp, Sebastian
A1  - Houben, Roland
A1  - Meierjohann, Svenja
T1  - BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1
JF  - Oncogenesis
N2  - Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.
KW  - melanoma
KW  - senescence
KW  - BRAF
KW  - tumor
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177261
VL  - 7
IS  - 71
ER  - 
TY  - JOUR
A1  - Thomas, Anna C.
A1  - Zeng, Zhiqiang
A1  - Rivière, Jean-Baptiste
A1  - O'Shaughnessy, Ryan
A1  - Al-Olabi, Lara
A1  - St.-Onge, Judith
A1  - Atherton, David J.
A1  - Aubert, Hélène
A1  - Bagazgoitia, Lorea
A1  - Barbarot, Sébastien
A1  - Bourrat, Emmanuelle
A1  - Chiaverini, Christine
A1  - Chong, W. Kling
A1  - Duffourd, Yannis
A1  - Glover, Mary
A1  - Groesser, Leopold
A1  - Hadj-Rabia, Smail
A1  - Hamm, Henning
A1  - Happle, Rudolf
A1  - Mushtaq, Imran
A1  - Lacour, Jean-Philippe
A1  - Waelchli, Regula
A1  - Wobser, Marion
A1  - Vabres, Pierre
A1  - Patton, E. Elizabeth
A1  - Kinsler, Veronica A.
T1  - Mosaic activating mutations in GNA11 and GNAQ are associated with phakomatosis pigmentovascularis and extensive dermal melanocytosis
JF  - Journal of Investigative Dermatology
N2  - Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Ga subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11\(^R183C\) and GNA11\(^Q209L\) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11\(^R183C\) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.
KW  - uveal melanoma
KW  - G Protein
KW  - dermal melanocytosis
KW  - Sturge-Weber syndrom
KW  - cesioflammea
KW  - germline
KW  - phakomatosis pigmentovascularis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189689
VL  - 136
IS  - 4
ER  -