% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Zucchini:294418,
      author       = {C. Zucchini and M. C. Manara and C. Cristalli and M.
                      Carrabotta and S. Greco and R. S. Pinca and C. Ferrari and
                      L. Landuzzi and M. Pasello and P.-L. Lollini and M.
                      Gambarotti and D. M. Donati and K. Scotlandi},
      title        = {{ROCK}2 deprivation leads to the inhibition of tumor growth
                      and metastatic potential in osteosarcoma cells through the
                      modulation of {YAP} activity.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {38},
      number       = {1},
      issn         = {0392-9078},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2024-02247},
      pages        = {503},
      year         = {2019},
      abstract     = {The treatment of metastatic osteosarcoma (OS) remains a
                      challenge for oncologists, and novel therapeutic strategies
                      are urgently needed. An understanding of the pathways that
                      regulate OS dissemination is required for the design of
                      novel treatment approaches. We recently identified
                      Rho-associated coiled-coil containing protein kinase 2
                      (ROCK2) as a crucial driver of OS cell migration. In this
                      study, we explored the impact of ROCK2 disruption on the
                      metastatic capabilities of OS cells and analyzed its
                      functional relationship with Yes-associated protein-1 (YAP),
                      the main transcriptional mediator of mechanotransduction
                      signaling.The effects of ROCK2 depletion on metastasis were
                      studied in NOD Scid gamma (NSG) mice injected with U-2OS
                      cells in which ROCK2 expression had been stably silenced.
                      Functional studies were performed in vitro in human U-2OS
                      cells and in three novel cell lines derived from
                      patient-derived xenografts (PDXs) by using standard methods
                      to evaluate malignancy parameters and signaling
                      transduction. The nuclear immunostaining of YAP and the
                      evaluation of its downstream targets Cysteine Rich
                      Angiogenic Inducer 6, Connective Tissue Growth Factor and
                      Cyclin D1 by quantitative PCR were performed to analyze YAP
                      activity. The effect of the expression and activity of ROCK2
                      and YAP on tumor progression was analyzed in 175 OS primary
                      tumors.The silencing of ROCK2 markedly reduced tumor growth
                      and completely abolished the metastatic ability of U-2OS
                      cells. The depletion of ROCK2, either by pharmacological
                      inhibition or silencing, induced a dose- and time-dependent
                      reduction in the nuclear expression and transcriptional
                      activity of YAP. The nuclear expression of YAP was observed
                      in 80/175 $(46\%)$ tumor samples and was significantly
                      correlated with worse patient prognosis and a higher
                      likelihood of metastasis and death. The use of verteporfin,
                      a molecule that specifically inhibits the TEAD-YAP
                      association, remarkably impaired the growth and migration of
                      OS cells in vitro. Moreover to inhibiting YAP activity, our
                      findings indicate that verteporfin also affects the ROCK2
                      protein and its functions.We describe the functional
                      connection between ROCK2 and YAP in the regulation of OS
                      cell migration and metastasis formation. These data provide
                      support for the use of verteporfin as a possible therapeutic
                      option to prevent OS cell dissemination.},
      keywords     = {Adaptor Proteins, Signal Transducing: genetics / Adaptor
                      Proteins, Signal Transducing: metabolism / Adolescent /
                      Animals / Bone Neoplasms: genetics / Bone Neoplasms:
                      metabolism / Bone Neoplasms: pathology / Bone Neoplasms:
                      therapy / Cell Line, Tumor / Cell Movement / Cell
                      Proliferation / Child / Disease Models, Animal / Female /
                      Heterografts / Humans / Immunohistochemistry / Kaplan-Meier
                      Estimate / Mice / Osteosarcoma: genetics / Osteosarcoma:
                      metabolism / Osteosarcoma: pathology / Osteosarcoma: therapy
                      / Prognosis / Protein Binding / RNA Interference /
                      Transcription Factors: genetics / Transcription Factors:
                      metabolism / Verteporfin: pharmacology / YAP-Signaling
                      Proteins / rho-Associated Kinases: genetics / rho-Associated
                      Kinases: metabolism / Metastasis (Other) / Osteosarcoma
                      (Other) / ROCK2 (Other) / Verteporfin (Other) / YAP (Other)
                      / Adaptor Proteins, Signal Transducing (NLM Chemicals) /
                      Transcription Factors (NLM Chemicals) / YAP-Signaling
                      Proteins (NLM Chemicals) / YAP1 protein, human (NLM
                      Chemicals) / Verteporfin (NLM Chemicals) / ROCK2 protein,
                      human (NLM Chemicals) / rho-Associated Kinases (NLM
                      Chemicals)},
      ddc          = {610},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31878963},
      pmc          = {pmc:PMC6933701},
      doi          = {10.1186/s13046-019-1506-3},
      url          = {https://inrepo02.dkfz.de/record/294418},
}