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  • 1
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    Abstract 2003: Oncogenic interplay of FUS-DDIT3 and YAP1 in myxoid liposarcoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2003-2003
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2003-2003
    Abstract: Introduction: Myxoid liposarcoma (MLS) represents the second most common subtype of liposarcoma. MLS is characterized by a chromosomal translocation t(12;16)(q13;p11) encoding a chimeric FUS-DDIT3 fusion gene. The resulting FUS-DDIT3 oncoprotein acts as a transcriptional dysregulator that was recently shown to mediate (i) IGF-IR/PI3K/AKT signaling and (ii) aberrant activation of the Hippo pathway effector YAP1 in MLS. This study was performed to analyze the functional interplay between IGF-IR/PI3K/AKT signals and aberrant YAP1 activity in MLS, aiming at a better functional understanding of MLS and the identification of specific molecular vulnerabilities. Experimental procedures: Immunohistochemical stainings of IGF-IR, IGF-II and YAP1 were performed in a cohort of MLS specimens (n=45). To study FUS-DDIT3-dependency in vitro, SCP-1 mesenchymal stem cells stably expressing FUS-DDIT3, and MLS cell lines expressing a doxycycline-inducible shRNA against FUS-DDIT3 were employed. Interactions between the IGF-IR/PI3K/AKT and Hippo/YAP1 pathways were investigated using RNAi approaches as well as the small molecule compounds BMS-754807 and BKM120; effects were analyzed by immunoblotting and TEAD luciferase reporter assays. To determine the impact of YAP1 in FUS-DDIT3-mediated oncogenic effects, qPCR analysis and adipogenic differentiation assays were performed. Results: Immunohistochemical analysis of human MLS tissue specimens demonstrated that expression of IGF-II and IGF-IR is associated with concomitant nuclear expression of YAP1 in a significant subset of MLS. Both, IGF-IR-dependent signals and YAP1 expression were shown to be functionally dependent on FUS-DDIT3. In MLS cell lines, inhibition of the IGF-IR/PI3K/AKT signaling cascade promoted downregulation of YAP1, accompanied by reduced TEAD transcriptional activity. Employing qPCR analyses, YAP1 was shown to co-regulate FUS-DDIT3 transcriptional targets and to be functionally involved in FUS-DDIT3-driven disruption of normal adipocytic differentiation. Conclusions: Our study provides evidence of a complex regulatory interplay in MLS with FUS-DDIT3-driven IGF-IR/PI3K/AKT signals acting as activators of nuclear YAP1 expression. Conversely, YAP1 contributes to shape FUS-DDIT3 effects on the MLS transcriptional landscape and functionally adds to an immature non-lipogenic phenotype. Our data contribute to the understanding of MLS biology and reveal specific molecular liabilities to be considered in therapeutic approaches of MLS. Citation Format: Ruth Berthold, Ilka Isfort, Jonas Breuer, Lorena Heinst, Thomas Kindler, Pierre Åman, Inga Grünewald, Eva Wardelmann, Thomas G. Grünewald, Florencia Cidre-Aranaz, Claudia Scholl, Stefan Fröhling, Marcel Trautmann, Wolfgang Hartmann. Oncogenic interplay of FUS-DDIT3 and YAP1 in myxoid liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2003.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2003
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    Recurrent CTNNB1 mutations in craniofacial osteomas
    Elsevier BV ; 2022
    In:  Modern Pathology Vol. 35, No. 4 ( 2022-04), p. 489-494
    Details
    In: Modern Pathology, Elsevier BV, Vol. 35, No. 4 ( 2022-04), p. 489-494
    Type of Medium: Online Resource
    ISSN: 0893-3952
    URL: Article
    DOI: 10.1038/s41379-021-00956-x
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 3
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    Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
    Springer Science and Business Media LLC ; 2022
    In:  Oncogenesis Vol. 11, No. 1 ( 2022-04-22)
    Details
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2022-04-22)
    Abstract: Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS-DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1´s precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    URL: Article
    DOI: 10.1038/s41389-022-00394-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 4
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    Abstract PR004: Fusion protein-driven IGF-IR signals deregulate hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 18_Supplement ( 2022-09-15), p. PR004-PR004
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 18_Supplement ( 2022-09-15), p. PR004-PR004
    Abstract: Introduction: Myxoid liposarcoma (MLS) is molecularly characterized by a recurrent chromosomal translocation which generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein, acting as a transcriptional dysregulator, has been shown to be essential in MLS pathogenesis, among others through deregulation of IGF-IR/PI3K/AKT signaling, but its exact mode of function remains incompletely understood. Recently, a particular reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was found in MLS; however, the molecular mechanism of FUS-DDIT3-dependent YAP1 activation and its contribution to MLS pathogenesis remain unclear. Experimental Procedures: The expression of IGF-IR and YAP1 was analyzed in a large cohort of MLS specimens by immunohistochemistry. In vitro analyses were performed employing a human mesenchymal stem cell system stably expressing FUS-DDIT3 and human MLS cell lines. RNA interference-based approaches, experiments with small-molecule kinase inhibitors, co-immunoprecipitation, proximity ligation assays, transcriptome sequencing and adipogenic differentiation assays were performed to determine the interplay of FUS-DDIT3, IGF-IR-dependent signals, and YAP1 in MLS cells. Results: Immunohistochemically, a significant subset of MLS samples showed concurrent expression of IGF-IR and nuclear YAP1. In vitro, FUS-DDIT3-driven IGF-IR signaling was found to promote stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1 in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate specific oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In differentiation assays, FUS-DDIT3 and YAP1 were found to cooperate in adipogenic differentiation arrest. Conclusions: Our study provides molecular insights into a complex FUS-DDIT3-driven network involving IGF-IR signals acting on Hippo/YAP1, and uncovers cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS. Citation Format: Ruth Berthold, Ilka Isfort, Cihan Erkut, Lorena Heinst, Inga Grünewald, Eva Wardelmann, Thomas Kindler, Pierre Åman, Thomas G.P. Grünewald, Florencia Cidre-Aranaz, Marcel Trautmann, Stefan Fröhling, Claudia Scholl, Wolfgang Hartmann. Fusion protein-driven IGF-IR signals deregulate hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR004.
    Type of Medium: Online Resource
    ISSN: 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.SARCOMAS22-PR004
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    SS18-SSX drives CREB activation in synovial sarcoma
    Springer Science and Business Media LLC ; 2022
    In:  Cellular Oncology Vol. 45, No. 3 ( 2022-06), p. 399-413
    Details
    In: Cellular Oncology, Springer Science and Business Media LLC, Vol. 45, No. 3 ( 2022-06), p. 399-413
    Abstract: Synovial sarcoma (SySa) is a rare soft tissue tumor characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein represents the major driver of the disease, acting as aberrant transcriptional dysregulator. Oncogenic mechanisms whereby SS18-SSX mediates sarcomagenesis are incompletely understood, and strategies to selectively target SySa cells remain elusive. Based on results of Phospho-Kinase screening arrays, we here investigate the functional and therapeutic relevance of the transcription factor CREB in SySa tumorigenesis. Methods Immunohistochemistry of phosphorylated CREB and its downstream targets (Rb, Cyclin D1, PCNA, Bcl-xL and Bcl-2) was performed in a large cohort of SySa. Functional aspects of CREB activity, including SS18-SSX driven circuits involved in CREB activation, were analyzed in vitro employing five SySa cell lines and a mesenchymal stem cell model. CREB mediated transcriptional activity was modulated by RNAi-mediated knockdown and small molecule inhibitors (666-15, KG-501, NASTRp and Ro 31-8220). Anti-proliferative effects of the CREB inhibitor 666-15 were tested in SySa avian chorioallantoic membrane and murine xenograft models in vivo. Results We show that CREB is phosphorylated and activated in SySa, accompanied by downstream target expression. Human mesenchymal stem cells engineered to express SS18-SSX promote CREB expression and phosphorylation. Conversely, RNAi-mediated knockdown of SS18-SSX impairs CREB phosphorylation in SySa cells. Inhibition of CREB activity reduces downstream target expression, accompanied by suppression of SySa cell proliferation and induction of apoptosis in vitro and in vivo . Conclusion In conclusion, our data underline an essential role of CREB in SySa tumorigenesis and provides evidence for molecular targeted therapies.
    Type of Medium: Online Resource
    ISSN: 2211-3428 , 2211-3436
    URL: Article
    DOI: 10.1007/s13402-022-00673-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 6
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    Abstract A027: Characterization of WEE1 kinase activity in myxoid liposarcoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 18_Supplement ( 2022-09-15), p. A027-A027
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 18_Supplement ( 2022-09-15), p. A027-A027
    Abstract: Introduction: Myxoid liposarcomas (MLS), malignant soft tissue tumors of adipocyte origin, are genetically characterized by a chromosomal t(12;16)(q13;p11) translocation encoding the chimeric FUS-DDIT3 fusion gene. The resulting fusion protein drives MLS pathogenesis via (dys-)regulation of oncogenic signaling pathways. Since FUS-DDIT3 is not selectively antagonizable, counteracting the oncogenic effects of FUS-DDIT3 fusion protein represents the most promising strategy to target MLS cells. In this study, we identified cell cycle checkpoint kinase WEE1 as FUS-DDIT3 depending effector and investigated the functional requirement for WEE1 kinase activity in MLS pathogenesis. Experimental Procedures: Characterization of WEE1 expression and kinase activity was performed in multiple MLS cell lines, cell lines derived from other liposarcoma subtypes and a mesenchymal stem cell system. Modulation of WEE1 signaling was carried out by means of small-molecule inhibitor Adavosertib (MK-1775) and RNA interference (RNAi)-mediated depletion, and effects were analyzed in immunoblots, cell proliferation assays and caspase 3/7 activity-based apoptosis assays in vitro. Results: Functional genomic RNAi screening uncovered dependence of FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines on WEE1 kinase activity. Additional expression analysis revealed increased WEE1 protein levels in MLS cell lines. Moreover, pharmacologic inhibition of WEE1 demonstrated significant reduction of MLS cell viability. Accordingly, functional loss of WEE1 by inhibition or RNAi-mediated depletion was found to induce DNA damage accompanied by unscheduled mitotic entry and cell death via activation of the apoptotic program in MLS cells. Conclusions: Our results identify WEE1 kinase activity as functional liability of FUS-DDIT3 expressing MLS cells and provide first evidence that overactive WEE1 signaling represents a promising target for therapeutic intervention in MLS. Citation Format: Lorena Heinst, Ruth Berthold, Ilka Isfort, Svenja Wosnig, Thomas Kindler, Pierre Åman, Eva Wardelmann, Claudia Scholl, Stefan Fröhling, Wolfgang Hartmann, Marcel Trautmann. Characterization of WEE1 kinase activity in myxoid liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A027.
    Type of Medium: Online Resource
    ISSN: 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.SARCOMAS22-A027
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract A031: Interplay of YAP1, β-catenin and the SS18-SSX fusion protein in synovial sarcoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 18_Supplement ( 2022-09-15), p. A031-A031
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 18_Supplement ( 2022-09-15), p. A031-A031
    Abstract: Introduction: Synovial sarcoma (SySa) is a rare soft-tissue malignancy characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives SySa pathogenesis by dysregulating gene transcription. As therapeutic targeting of SS18-SSX is notoriously difficult, the identification of SS18-SSX-dependent pathomechanisms may uncover novel molecular vulnerabilities. Since previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional co-regulators YAP1/TAZ and β-catenin, this study examined a potential crosstalk between these effectors in SySa. Experimental Procedures: Nuclear abundance of YAP1/TAZ and β-catenin was analyzed by immunohistochemistry in a large cohort of SySa tissue specimens. Two SySa cell lines were employed to modulate YAP1/TAZ/β-catenin transcriptional activity by RNAi-mediated knockdown, small molecule inhibitors, and overexpression vectors in vitro. Changes in transcriptional activity were determined via luciferase reporter assays. As YAP1 and β-catenin showed highest interdependence, co-immunoprecipitation experiments were performed to investigate their interplay with the SS18-SSX fusion protein in SySa cells. Results: Immunohistochemically, a substantial subset of SySa tissue specimens showed concurrent nuclear accumulation of YAP1/TAZ and β-catenin. In vitro, SS18-SSX was found to promote YAP1/TAZ and β-catenin transcriptional activity. RNAi-mediated knockdown of YAP1, TAZ or β-catenin and small molecule inhibitor treatment mutually downregulated TEAD and TCF luciferase reporter activity, while expression of hyperactive variants led to a reciprocal luciferase reporter induction. Finally, co-immunoprecipitation assays demonstrated nuclear co-localization of SS18-SSX with YAP1 and β-catenin in SySa cell lines. Conclusions: This study reveals an interdependency between YAP1 and β-catenin activation and a complex interplay with the SySa-specific SS18-SSX fusion protein. Citation Format: Ilka Isfort, Ruth Berthold, Lorena Heinst, Eva Wardelmann, Marcel Trautmann, Wolfgang Hartmann. Interplay of YAP1, β-catenin and the SS18-SSX fusion protein in synovial sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl ):Abstract nr A031.
    Type of Medium: Online Resource
    ISSN: 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.SARCOMAS22-A031
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    Interdependence of SS18-SSX–driven YAP1 and β-Catenin Activation in Synovial Sarcoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Research Vol. 21, No. 6 ( 2023-06-01), p. 535-547
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 6 ( 2023-06-01), p. 535-547
    Abstract: Synovial sarcoma, a rare malignant soft tissue tumor, is characterized by a specific chromosomal translocation t(X;18). The resulting chimeric SS18-SSX fusion protein drives synovial sarcoma pathogenesis by integrating into the BAF complex and dysregulating gene transcription. Because previous functional analyses revealed a connection between SS18-SSX and the activity of the transcriptional coregulators YAP1/TAZ and β-catenin, respectively, this study examined a potential interdependence between these essential effector proteins in synovial sarcoma. In a large cohort of synovial sarcoma tissue specimens, IHC analyses revealed a substantial subset of synovial sarcoma with concurrent nuclear accumulation of YAP1/TAZ and β-catenin. In vitro, small-molecule inhibitor treatment, RNAi-mediated knockdown, and vector-based overexpression assays demonstrated that YAP1, TAZ, and β-catenin transcriptional activity is not only stimulated by the SS18-SSX fusion protein, but that they also mutually enhance each other's activation. These analyses showed the highest cooperative effect with overexpression of YAP1 in combination with β-catenin. Coimmunoprecipitation experiments detected nuclear interactions between YAP1, β-catenin, and the SS18-SSX fusion protein, the latter being an integral part of the BAF complex. Disruption of BAF complex assembly affected the coregulation of YAP1 and β-catenin, indicating that this chromatin remodeling complex plays a crucial role for interdependent YAP1 and β-catenin activation in synovial sarcoma cells. Implications: This study provides deeper insights into synovial sarcoma tumor biology demonstrating a mutual dependence between YAP1/TAZ and β-catenin transcriptional activity and a complex interplay with the SS18-SSX fusion protein within the BAF complex.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-22-0588
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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