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SMAD dependent signaling plays a detrimental role in a fly model of SMARCB1-deficiency and the biology of atypical teratoid/rhabdoid tumors

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Abstract

Atypical teratoid/rhabdoid tumors (ATRT) are highly malignant brain tumors arising in young children. The majority of ATRT is characterized by inactivation of the chromatin remodeling complex member SMARCB1 (INI1/hSNF5). Little is known, however, on downstream pathways involved in the detrimental effects of SMARCB1 deficiency which might also represent targets for treatment. Using Drosophila melanogaster and the Gal4-UAS system, modifier screens were performed in order to identify the role of SMAD dependent signaling in the lethal phenotype associated with knockdown of snr1, the fly homolog of SMARCB1. Expression and functional role of human homologs was next investigated in ATRT tumor samples and SMARCB1-deficient rhabdoid tumor cells. The lethal phenotype associated with snr1 knockdown in Drosophila melanogaster could be shifted to later stages of development upon additional knockdown of several decapentaplegic pathway members including Smox, and Med. Similarly, the transforming growth factor beta (TGFbeta) receptor type I kinase inhibitor SB431542 ameliorated the detrimental effect of snr1 knockdown in the fruit fly. Examination of homologs of candidate decapentaplegic pathway members in human SMARCB1-deficent ATRT samples revealed SMAD3 and SMAD6 to be over-expressed. In SMARCB1-deficent rhabdoid tumor cells, siRNA-mediated silencing of SMAD3 or SMAD6 expression reduced TGFbeta signaling activity and resulted in decreased proliferation. Similar results were obtained upon pharmacological inhibition of TGFbeta signaling using SB431542. Our data suggest that SMAD dependent signaling is involved in the detrimental effects of SMARCB1-deficiency and provide a rationale for the investigation of TGFbeta targeted treatments in ATRT.

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Acknowledgements

This work was supported by Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Münster (Ha3/019/15), Deutsche Forschungsgemeinschaft (Pa 328/7) and Deutsche Krebshilfe (110266). The EU-RHAB registry is supported by Deutsche Kinderkrebsstiftung.

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Authors and Affiliations

  1. Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany

    Astrid Jeibmann, Jacqueline Schulz, Kristin Eikmeier, Katharina Thiel, Isabel Tegeder, Werner Paulus & Martin Hasselblatt

  2. Division of Pediatric Neurooncology, German Cancer Research Center DKFZ, Heidelberg, Germany

    Pascal D. Johann, Stefan M. Pfister & Marcel Kool

  3. German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany

    Pascal D. Johann & Stefan M. Pfister

  4. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Pascal D. Johann & Stefan M. Pfister

  5. Department of Psychiatry, University Hospital Münster, Münster, Germany

    Oliver Ambrée

  6. Swabian Childrens’ Cancer Center, Childrens’ Hospital Augsburg and EU-RHAB Registry Working Group, Augsburg, Germany

    Michael C. Frühwald

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  1. Astrid Jeibmann
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Correspondence to Martin Hasselblatt.

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Jeibmann, A., Schulz, J., Eikmeier, K. et al. SMAD dependent signaling plays a detrimental role in a fly model of SMARCB1-deficiency and the biology of atypical teratoid/rhabdoid tumors. J Neurooncol 131, 477–484 (2017). https://doi.org/10.1007/s11060-016-2326-3

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