@article{WegertBausenweinKneitzetal.2011,
  author    = {Wegert, Jenny and Bausenwein, Sabrina and Kneitz, Susanne and Roth, Sabine and Graf, Norbert and Geissinger, Eva and Gessler, Manfred},
  title     = {Retinoic acid pathway activity in Wilms tumors and characterization of biological responses in vitro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69137},
  year      = {2011},
  abstract  = {Background: Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90\% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. Results: The association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/ intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however. Conclusions: Altered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.},
  subject      = {Krebs},
  language  = {en}
}
@article{JessenKressBaluapurietal.2020,
  author    = {Jessen, Christina and Kreß, Julia K. C. and Baluapuri, Apoorva and Hufnagel, Anita and Schmitz, Werner and Kneitz, Susanne and Roth, Sabine and Marquardt, Andr{\´e} and Appenzeller, Silke and Ade, Casten P. and Glutsch, Valerie and Wobser, Marion and Friedmann-Angeli, Jos{\´e} Pedro and Mosteo, Laura and Goding, Colin R. and Schilling, Bastian and Geissinger, Eva and Wolf, Elmar and Meierjohann, Svenja},
  title     = {The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression},
  series = {Oncogene},
  volume    = {39},
  journal   = {Oncogene},
  issn      = {0950-9232},
  doi       = {10.1038/s41388-020-01477-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235064},
  pages     = {6841-6855},
  year      = {2020},
  abstract  = {The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.},
  language  = {en}
}
@article{MainzSarhanRothetal.2022,
  author    = {Mainz, Laura and Sarhan, Mohamed A. F. E. and Roth, Sabine and Sauer, Ursula and Maurus, Katja and Hartmann, Elena M. and Seibert, Helen-Desiree and Rosenwald, Andreas and Diefenbacher, Markus E. and Rosenfeldt, Mathias T.},
  title     = {Autophagy blockage reduces the incidence of pancreatic ductal adenocarcinoma in the context of mutant Trp53},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {10},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2022.785252},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266005},
  year      = {2022},
  abstract  = {Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53\(^{R172H}\)) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.},
  language  = {en}
}