Context-dependent modulation of aggressiveness of pediatric tumors by individual oncogenic RAS isoforms

  1. Bauer, Julia ORCID logo
  2. Cuvelier, Nicole
  3. Ragab, Nada
  4. Simon-Keller, Katja
  5. Nitzki, Frauke
  6. Geyer, Natalie
  7. Botermann, Dominik Simon ORCID logo
  8. Elmer, Dominik P. ORCID logo
  9. Rosenberger, Albert ORCID logo
  10. Rando, Thomas A.
  11. Biressi, Stefano
  12. Fagin, James ORCID logo
  13. Saur, Dieter ORCID logo
  14. Dullin, Christian ORCID logo
  15. Schildhaus, Hans-Ulrich
  16. Schulz-Schaeffer, Walter
  17. Aberger, Fritz ORCID logo
  18. Uhmann, Anja
  19. Hahn, Heidi ORCID logo

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1000 Titel
  • Context-dependent modulation of aggressiveness of pediatric tumors by individual oncogenic RAS isoforms
1000 Autor/in
  1. Bauer, Julia |
  2. Cuvelier, Nicole |
  3. Ragab, Nada |
  4. Simon-Keller, Katja |
  5. Nitzki, Frauke |
  6. Geyer, Natalie |
  7. Botermann, Dominik Simon |
  8. Elmer, Dominik P. |
  9. Rosenberger, Albert |
  10. Rando, Thomas A. |
  11. Biressi, Stefano |
  12. Fagin, James |
  13. Saur, Dieter |
  14. Dullin, Christian |
  15. Schildhaus, Hans-Ulrich |
  16. Schulz-Schaeffer, Walter |
  17. Aberger, Fritz |
  18. Uhmann, Anja |
  19. Hahn, Heidi |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-06-25
1000 Erschienen in
1000 Quellenangabe
  • 40(31):4955-4966
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41388-021-01904-4 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342309/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • A prototypic pediatric cancer that frequently shows activation of RAS signaling is embryonal rhabdomyosarcoma (ERMS). ERMS also show aberrant Hedgehog (HH)/GLI signaling activity and can be driven by germline mutations in this pathway. We show, that in ERMS cell lines derived from sporadic tumors i.e. from tumors not caused by an inherited genetic variant, HH/GLI signaling plays a subordinate role, because oncogenic mutations in HRAS, KRAS, or NRAS (collectively named oncRAS) inhibit the main HH target GLI1 via the MEK/ERK-axis, but simultaneously increase proliferation and tumorigenicity. oncRAS also modulate expression of stem cell markers in an isoform- and context-dependent manner. In Hh-driven murine ERMS that are caused by a Patched mutation, oncHRAS and mainly oncKRAS accelerate tumor development, whereas oncNRAS induces a more differentiated phenotype. These features occur when the oncRAS mutations are induced at the ERMS precursor stage, but not when induced in already established tumors. Moreover, in contrast to what is seen in human cell lines, oncRAS mutations do not alter Hh signaling activity and marginally affect expression of stem cell markers. Together, all three oncRAS mutations seem to be advantageous for ERMS cell lines despite inhibition of HH signaling and isoform-specific modulation of stem cell markers. In contrast, oncRAS mutations do not inhibit Hh-signaling in Hh-driven ERMS. In this model, oncRAS mutations seem to be advantageous for specific ERMS populations that occur within a specific time window during ERMS development. In addition, this window may be different for individual oncRAS isoforms, at least in the mouse.
1000 Sacherschließung
lokal Gene Expression Regulation, Neoplastic [MeSH]
lokal Paediatric cancer
lokal Age Factors [MeSH]
lokal Disease Progression [MeSH]
lokal Patched-1 Receptor/genetics [MeSH]
lokal Oncogenes [MeSH]
lokal MAP Kinase Signaling System [MeSH]
lokal Neoplasms/metabolism [MeSH]
lokal Genes, ras [MeSH]
lokal Neoplasms/pathology [MeSH]
lokal Disease Models, Animal [MeSH]
lokal Neoplastic Stem Cells [MeSH]
lokal Mutation [MeSH]
lokal Cell Transformation, Neoplastic/metabolism [MeSH]
lokal Humans [MeSH]
lokal Cell Transformation, Neoplastic/genetics [MeSH]
lokal Animals [MeSH]
lokal Disease Susceptibility [MeSH]
lokal Mice, Knockout [MeSH]
lokal Protein Isoforms/genetics [MeSH]
lokal Mice [MeSH]
lokal Article
lokal Neoplasms/etiology [MeSH]
lokal Zinc Finger Protein GLI1/genetics [MeSH]
lokal Cancer genetics
lokal Gene Expression Profiling [MeSH]
lokal Zinc Finger Protein GLI1/metabolism [MeSH]
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0001-5390-1855|https://frl.publisso.de/adhoc/uri/Q3V2ZWxpZXIsIE5pY29sZQ==|https://frl.publisso.de/adhoc/uri/UmFnYWIsIE5hZGE=|https://frl.publisso.de/adhoc/uri/U2ltb24tS2VsbGVyLCBLYXRqYQ==|https://frl.publisso.de/adhoc/uri/Tml0emtpLCBGcmF1a2U=|https://frl.publisso.de/adhoc/uri/R2V5ZXIsIE5hdGFsaWU=|https://orcid.org/0000-0001-7747-7147|https://orcid.org/0000-0003-2038-6775|https://orcid.org/0000-0001-7848-1332|https://frl.publisso.de/adhoc/uri/UmFuZG8sIFRob21hcyBBLg==|https://frl.publisso.de/adhoc/uri/QmlyZXNzaSwgU3RlZmFubw==|https://orcid.org/0000-0002-2365-2517|https://orcid.org/0000-0001-5874-0210|https://orcid.org/0000-0003-4297-8077|https://frl.publisso.de/adhoc/uri/U2NoaWxkaGF1cywgSGFucy1VbHJpY2g=|https://frl.publisso.de/adhoc/uri/U2NodWx6LVNjaGFlZmZlciwgV2FsdGVy|https://orcid.org/0000-0003-2009-6305|https://frl.publisso.de/adhoc/uri/VWhtYW5uLCBBbmph|https://orcid.org/0000-0002-3646-4566
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1000 Erstellt am 2023-04-27T10:21:19.549+0200
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1000 Zuletzt bearbeitet Thu Oct 19 15:23:43 CEST 2023
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