TY  - JOUR
A1  - Meierjohann, Svenja
T1  - Hypoxia independent drivers of melanoma angiogenesis
JF  - Frontiers in Oncology
N2  - Tumor angiogenesis is a process which is traditionally regarded as the tumor’s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a pre-requisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia-independent mechanisms of tumor angiogenesis in melanoma.
KW  - melanoma
KW  - angiogenesis
KW  - hypoxia-independent
KW  - reactive oxygen species
KW  - NF-κB
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125586
VL  - 5
IS  - 120
ER  - 
TY  - JOUR
A1  - Haydn, Johannes M.
A1  - Hufnagel, Anita
A1  - Grimm, Johannes
A1  - Maurus, Katja
A1  - Schartl, Manfred
A1  - Meierjohann, Svenja
T1  - The MAPK pathway as an apoptosis enhancer in melanoma
JF  - Oncotarget
N2  - Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAFV600E–mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAFV600E-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.
KW  - PI3K
KW  - melanoma
KW  - RAS
KW  - chemotherapy resistance
KW  - crosstalk
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120649
SN  - 1949-2553
VL  - 5
IS  - 13
ER  - 
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  -