Moll, Ute M.

[["dc.bibliographiccitation.artnumber","4019"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Isermann, Tamara"],["dc.contributor.author","Şener, Özge Çiçek"],["dc.contributor.author","Stender, Adrian"],["dc.contributor.author","Klemke, Luisa"],["dc.contributor.author","Winkler, Nadine"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.author","Li, Jinyu"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.date.accessioned","2021-08-12T07:44:56Z"],["dc.date.available","2021-08-12T07:44:56Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract The vast majority of human tumors with p53 mutations undergo loss of the remaining wildtype p53 allele (loss-of-heterozygosity, p53LOH). p53LOH has watershed significance in promoting tumor progression. However, driving forces for p53LOH are poorly understood. Here we identify the repressive WTp53–HSF1 axis as one driver of p53LOH. We find that the WTp53 allele in AOM/DSS chemically-induced colorectal tumors (CRC) of p53 R248Q/+ mice retains partial activity and represses heat-shock factor 1 (HSF1), the master regulator of the proteotoxic stress response (HSR) that is ubiquitously activated in cancer. HSR is critical for stabilizing oncogenic proteins including mutp53. WTp53-retaining CRC tumors, tumor-derived organoids and human CRC cells all suppress the tumor-promoting HSF1 program. Mechanistically, retained WTp53 activates CDKN1A /p21, causing cell cycle inhibition and suppression of E2F target MLK3. MLK3 links cell cycle with the MAPK stress pathway to activate the HSR response. In p53 R248Q/+ tumors WTp53 activation by constitutive stress represses MLK3, thereby weakening the MAPK-HSF1 response necessary for tumor survival. This creates selection pressure for p53LOH which eliminates the repressive WTp53-MAPK-HSF1 axis and unleashes tumor-promoting HSF1 functions, inducing mutp53 stabilization enabling invasion."],["dc.description.sponsorship","Open-Access-Finanzierung durch die Universitätsmedizin Göttingen 2021"],["dc.identifier.doi","10.1038/s41467-021-24064-1"],["dc.identifier.pii","24064"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88334"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation.eissn","2041-1723"],["dc.rights","CC BY 4.0"],["dc.title","Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Oncology"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Klemke, Luisa"],["dc.contributor.author","Fehlau, Clara F."],["dc.contributor.author","Winkler, Nadine"],["dc.contributor.author","Toboll, Felicia"],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Moll, Ute M."],["dc.contributor.author","Schulz-Heddergott, Ramona"],["dc.date.accessioned","2021-08-12T07:45:46Z"],["dc.date.available","2021-08-12T07:45:46Z"],["dc.date.issued","2021"],["dc.description.abstract","Missense p53 mutations (mutp53) occur in approx. 70% of pancreatic ductal adenocarcinomas (PDAC). Typically, mutp53 proteins are aberrantly stabilized by Hsp90/Hsp70/Hsp40 chaperone complexes. Notably, stabilization is a precondition for specific mutp53 alleles to acquire powerful neomorphic oncogenic gain-of-functions (GOFs) that promote tumor progression in solid cancers mainly by increasing invasion and metastasis. In colorectal cancer (CRC), we recently established that the common hotspot mutants mutp53 R248Q and mutp53 R248W exert GOF activities by constitutively binding to and hyperactivating STAT3. This results in increased proliferation and invasion in an autochthonous CRC mouse model and correlates with poor survival in patients. Comparing a panel of p53 missense mutations in a series of homozygous human PDAC cell lines, we show here that, similar to CRC, the mutp53 R248W protein again undergoes a strong Hsp90-mediated stabilization and selectively promotes migration. Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. In response to mutp53 depletion, only mutp53 R248W harboring PDAC cells show STAT3 de-phosphorylation and reduced migration, again suggesting an allele-specific GOF in this cancer entity, similar to CRC. Moreover, mutp53 R248W also exhibits the strongest constitutive complex formation with phosphorylated STAT3. The selective mutp53 R248W GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53 R248W -containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities."],["dc.description.abstract","Missense p53 mutations (mutp53) occur in approx. 70% of pancreatic ductal adenocarcinomas (PDAC). Typically, mutp53 proteins are aberrantly stabilized by Hsp90/Hsp70/Hsp40 chaperone complexes. Notably, stabilization is a precondition for specific mutp53 alleles to acquire powerful neomorphic oncogenic gain-of-functions (GOFs) that promote tumor progression in solid cancers mainly by increasing invasion and metastasis. In colorectal cancer (CRC), we recently established that the common hotspot mutants mutp53 R248Q and mutp53 R248W exert GOF activities by constitutively binding to and hyperactivating STAT3. This results in increased proliferation and invasion in an autochthonous CRC mouse model and correlates with poor survival in patients. Comparing a panel of p53 missense mutations in a series of homozygous human PDAC cell lines, we show here that, similar to CRC, the mutp53 R248W protein again undergoes a strong Hsp90-mediated stabilization and selectively promotes migration. Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. In response to mutp53 depletion, only mutp53 R248W harboring PDAC cells show STAT3 de-phosphorylation and reduced migration, again suggesting an allele-specific GOF in this cancer entity, similar to CRC. Moreover, mutp53 R248W also exhibits the strongest constitutive complex formation with phosphorylated STAT3. The selective mutp53 R248W GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53 R248W -containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3389/fonc.2021.642603"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/88548"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-448"],["dc.relation.eissn","2234-943X"],["dc.relation.orgunit","Institut für Molekulare Onkologie"],["dc.rights","CC BY 4.0"],["dc.title","The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]