Kramer, Frank

[["dc.bibliographiccitation.journal","Cancer Research"],["dc.bibliographiccitation.volume","71"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Rave-Fränk, Margret"],["dc.contributor.author","Scharf, Jens-Gerd"],["dc.contributor.author","Burfeind, Peter"],["dc.contributor.author","Becker, Heinz"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Ried, Thomas"],["dc.date.accessioned","2018-11-07T08:57:01Z"],["dc.date.available","2018-11-07T08:57:01Z"],["dc.date.issued","2011"],["dc.identifier.doi","10.1158/1538-7445.AM2011-2508"],["dc.identifier.isi","000209701302047"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/23286"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.publisher.place","Philadelphia"],["dc.relation.issn","1538-7445"],["dc.relation.issn","0008-5472"],["dc.title","Identification of potential relevant pathways and genes for resistance to chemoradiotherapy in colorectal cancer cells"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1481"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Molecular Cancer Research"],["dc.bibliographiccitation.lastpage","1490"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Reineke, Sebastian"],["dc.contributor.author","Möller, Janneke"],["dc.contributor.author","Auslander, Noam"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Hu, Yue"],["dc.contributor.author","Beissbarth, Tim"],["dc.contributor.author","Wolff, Hendrik A."],["dc.contributor.author","Rave-Fränk, Margret"],["dc.contributor.author","Heßmann, Elisabeth"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ghadimi, B. Michael"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Ried, Thomas"],["dc.contributor.author","Grade, Marian"],["dc.date.accessioned","2020-12-10T18:37:47Z"],["dc.date.available","2020-12-10T18:37:47Z"],["dc.date.issued","2017"],["dc.description.abstract","Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481-90. ©2017 AACR."],["dc.identifier.doi","10.1158/1541-7786.MCR-17-0205"],["dc.identifier.eissn","1557-3125"],["dc.identifier.issn","1541-7786"],["dc.identifier.pmid","28811361"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77090"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation.eissn","1557-3125"],["dc.relation.issn","1541-7786"],["dc.title","Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","247"],["dc.bibliographiccitation.lastpage","247"],["dc.contributor.author","Camps, Jordi"],["dc.contributor.author","Hummon, Amanda H."],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Pitt, Jason J."],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Nguyen, Quang T."],["dc.contributor.author","Ghadimi, B. Michael"],["dc.contributor.author","Difilippantonio, Michael J."],["dc.contributor.author","Beissbarth, Tim"],["dc.contributor.author","Caplen, Natasha J."],["dc.contributor.author","Ried, Thomas"],["dc.date.accessioned","2022-06-08T07:57:08Z"],["dc.date.available","2022-06-08T07:57:08Z"],["dc.date.issued","2014"],["dc.identifier.doi","10.1158/1538-7445.AM10-247"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/110005"],["dc.notes.intern","DOI-Import GROB-575"],["dc.publisher","American Association for Cancer Research"],["dc.relation.conference","Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC"],["dc.title","Abstract 247: A functional genomics and a systems biology approach identify POMP as a potential therapeutic target for colorectal cancer"],["dc.type","conference_paper"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1184"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","International Journal of Radiation Oncology*Biology*Physics"],["dc.bibliographiccitation.lastpage","1192"],["dc.bibliographiccitation.volume","78"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Rave-Fränk, Margret"],["dc.contributor.author","Scharf, Jens-Gerd"],["dc.contributor.author","Burfeind, Peter"],["dc.contributor.author","Becker, Heinz"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Ried, Thomas"],["dc.contributor.author","Grade, Marian"],["dc.date.accessioned","2018-11-07T08:36:51Z"],["dc.date.available","2018-11-07T08:36:51Z"],["dc.date.issued","2010"],["dc.description.abstract","Purpose: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need. Methods and Materials: To establish in vitro models for studying the molecular basis of this heterogeneous tumor response, we exposed 12 colorectal cancer cell lines to 3 mu M of 5-fluorouracil and 2 Gy of radiation. The differences in treatment sensitivity were then correlated with the pretherapeutic gene expression profiles of these cell lines. Results: We observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q < .05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. Conclusion: We are the first to report a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells. We anticipate that this analysis will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors. (C) 2010 Elsevier Inc."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [KFO 179]"],["dc.identifier.doi","10.1016/j.ijrobp.2010.06.023"],["dc.identifier.isi","000283963100030"],["dc.identifier.pmid","20970032"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6106"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/18405"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Inc"],["dc.relation.issn","0360-3016"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","A GENE EXPRESSION SIGNATURE FOR CHEMORADIOSENSITIVITY OF COLORECTAL CANCER CELLS"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Cancer Research"],["dc.bibliographiccitation.volume","71"],["dc.contributor.author","Kendziorra, Emil"],["dc.contributor.author","Ahlborn, Kerstin"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Rave-Fränk, Margret"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Ebner, Reinhard"],["dc.contributor.author","Becker, Heinz"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Pukrop, Tobias"],["dc.contributor.author","Ried, Thomas"],["dc.contributor.author","Grade, Marian"],["dc.date.accessioned","2018-11-07T08:57:01Z"],["dc.date.available","2018-11-07T08:57:01Z"],["dc.date.issued","2011"],["dc.identifier.doi","10.1158/1538-7445.AM2011-2490"],["dc.identifier.isi","000209701302028"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/23287"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.publisher.place","Philadelphia"],["dc.relation.issn","1538-7445"],["dc.relation.issn","0008-5472"],["dc.title","Silencing of TCF7L2 sensitizes Wnt/beta-catenin signaling-dependent colorectal cancer cells to radiation"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","997"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","International Journal of Cancer"],["dc.bibliographiccitation.lastpage","1007"],["dc.bibliographiccitation.volume","134"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Roesler, Birte"],["dc.contributor.author","Bielfeld, Christian"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Wolff, Hendrik Andreas"],["dc.contributor.author","Rave-Fränk, Margret"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Kitz, Julia"],["dc.contributor.author","Wienands, Juergen"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Ebner, Reinhard"],["dc.contributor.author","Ried, Thomas"],["dc.contributor.author","Grade, Marian"],["dc.date.accessioned","2018-11-07T09:44:52Z"],["dc.date.available","2018-11-07T09:44:52Z"],["dc.date.issued","2014"],["dc.description.abstract","Increased activity of signal transducer and activator of transcription 3 (STAT3) is common in human malignancies, including colorectal cancers (CRCs). We have recently reported that STAT3 gene expression correlates with resistance of CRC cell lines to 5-fluorouracil (5-FU)-based chemoradiotherapy (CT/RT). This is of considerable clinical importance, because a large proportion of rectal cancers are resistant to preoperative multimodal treatment. To test whether STAT3 contributes to CT/RT-resistance, we first confirmed that STAT3 protein expression correlated positively with increasing resistance. While STAT3 was not constitutively active, stimulation with interleukin-6 (IL-6) resulted in remarkably higher expression levels of phosphorylated STAT3 in CT/RT-resistant cell lines. A similar result was observed when we determined IL-6-induced expression levels of phosphorylated STAT3 following irradiation. Next, STAT3 was inhibited in SW480 and SW837 using siRNA, shRNA and the small-molecule inhibitor STATTIC. Successful silencing and inhibition of phosphorylation was confirmed using Western blot analysis and a luciferase reporter assay. RNAi-mediated silencing as well as STATTIC treatment resulted in significantly decreased clonogenic survival following exposure to 3 mu M of 5-FU and irradiation in a dose-dependent manner, with dose-modifying factors of 1.3-2.5 at a surviving fraction of 0.37. Finally, STAT3 inhibition led to a profound CT/RT-sensitization in a subcutaneous xenograft model, with a significantly delayed tumor regrowth in STATTIC-treated mice compared with control animals. These results highlight a potential role of STAT3 in mediating treatment resistance and provide first proof of concept that STAT3 represents a promising novel molecular target for sensitizing resistant rectal cancers to CT/RT. What's new? A considerable percentage of rectal cancers are resistant to preoperative chemoradiotherapy, which exposes patients to the potential side effects of both irradiation and chemotherapy without clear benefits. In this study, IL-6-stimulated expression levels of phosphorylated STAT3 were remarkably higher in chemoradiotherapy-resistant colorectal cancer cell lines. RNAi- and small molecule-mediated STAT3 inhibition sensitized to chemoradiotherapy in vitro in a dose-dependent manner, which led to a profound chemoradiotherapy-sensitization in a subcutaneous xenograft model. These results highlight a potential role of STAT3 in treatment resistance, and provide first proof of concept that STAT3 represents a promising novel molecular target for sensitizing resistant rectal cancers to chemoradiotherapy."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaf [KFO 179: GR 3376/1-1, GR 3376/1-2]"],["dc.identifier.doi","10.1002/ijc.28429"],["dc.identifier.isi","000327889700029"],["dc.identifier.pmid","23934972"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34492"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.relation.issn","1097-0215"],["dc.relation.issn","0020-7136"],["dc.title","STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","1"],["dc.bibliographiccitation.journal","Molecular Cancer"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Hummon, Amanda B."],["dc.contributor.author","Pitt, Jason J."],["dc.contributor.author","Camps, Jordi"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Skube, Susan B."],["dc.contributor.author","Huppi, Konrad"],["dc.contributor.author","Jones, Tamara L."],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Difilippantonio, Michael J."],["dc.contributor.author","Ried, Thomas"],["dc.contributor.author","Caplen, Natasha J."],["dc.date.accessioned","2018-11-07T09:14:27Z"],["dc.date.available","2018-11-07T09:14:27Z"],["dc.date.issued","2012"],["dc.description.abstract","Background: Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival. Results: A small-scale RNAi screen of similar to 400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently CASP8AP2/FLASH. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of CASP8AP2/FLASH resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non-canonical polyA variants of these transcripts. Silencing of CASP8AP2/FLASH also mediated enrichment of changes in the expression of targets of the NF kappa B and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of CASP8AP2/FLASH silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/beta-catenin pathway. Conclusions: We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene NEFH."],["dc.description.sponsorship","NIH, National Cancer Institute, Center for Cancer Research; NCI"],["dc.identifier.doi","10.1186/1476-4598-11-1"],["dc.identifier.isi","000301603300001"],["dc.identifier.pmid","22216762"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/7195"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/27412"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1476-4598"],["dc.rights","CC BY 2.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.0"],["dc.title","Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1824"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Carcinogenesis"],["dc.bibliographiccitation.lastpage","1831"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","Kendziorra, Emil"],["dc.contributor.author","Ahlborn, Kerstin"],["dc.contributor.author","Spitzner, Melanie"],["dc.contributor.author","Rave-Fränk, Margret"],["dc.contributor.author","Emons, Georg"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Kramer, Frank"],["dc.contributor.author","Wolff, Hendrik Andreas"],["dc.contributor.author","Becker, Heinz"],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Ebner, Reinhard"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Pukrop, Tobias"],["dc.contributor.author","Ried, Thomas"],["dc.contributor.author","Grade, Marian"],["dc.date.accessioned","2018-11-07T08:49:29Z"],["dc.date.available","2018-11-07T08:49:29Z"],["dc.date.issued","2011"],["dc.description.abstract","A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a beta-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by gamma H2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [KFO 179]"],["dc.identifier.doi","10.1093/carcin/bgr222"],["dc.identifier.isi","000297157700009"],["dc.identifier.pmid","21983179"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/21469"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0143-3334"],["dc.title","Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]