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SMARCB1 Loss in Poorly Differentiated Chordomas Drives Tumor Progression

  • Tara A. Walhart
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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  • Bryanna Vacca
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina

    Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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  • J. Austin Hepperla
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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  • Samera H. Hamad
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina

    Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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  • James Petrongelli
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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  • Yemin Wang
    Affiliations
    Department of Pathology and Laboratory Medicine, University of British Columbia, and Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada
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  • L. Erin McKean
    Affiliations
    Department of Otolaryngology and Neurosurgery, University of Michigan, Ann Arbor, Michigan
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  • Michelle Moksa
    Affiliations
    Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; and Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
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  • Qi Cao
    Affiliations
    Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; and Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
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  • Stephen Yip
    Affiliations
    Department of Pathology and Laboratory Medicine, University of British Columbia, and Department of Molecular Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada
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  • Martin Hirst
    Affiliations
    Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; and Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, British Columbia, Canada
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  • Bernard E. Weissman
    Correspondence
    Address correspondence to Bernard E. Weissman, Ph.D., Lineberger Comprehensive Cancer Center, University of North Carolina, Room 31-322, Chapel Hill, NC 27599-7295.
    Affiliations
    Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina

    Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina

    Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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Published:January 16, 2023DOI:https://doi.org/10.1016/j.ajpath.2022.12.012
      Poorly differentiated (PD) chordoma is a rare, aggressive tumor originating from notochordal tissue, with limited therapeutic options. SMARCB1, a core component of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes, is the most frequently mutated gene. To determine the impact of SMARCB1 re-expression on cell growth and gene expression, two SMARCB1-negative PD chordoma cell lines with an inducible SMARCB1 expression system were generated. After 72 hours of induction of SMARCB1, continued growth of both SMARCB1-negative PD chordoma cell lines was observed. This result contrasted with those observed with SMARCB1-negative rhabdoid cell lines in which SMARCB1 re-expression caused the rapid inhibition of growth. We found that the lack of growth inhibition may arise from the loss of CDKN2A (p16INK4A) expression in PD chordoma cell lines. RNA-sequencing of cell lines after SMARCB1 re-expression showed a down-regulation for rRNA and RNA processing as well as metabolic processing and increased expression of genes involved in cell adhesion, cell migration, and development. Taken together, these data establish that SMARCB1 re-expression in PD chordomas alters the repertoire of SWI/SNF complexes, perhaps restoring those associated with cellular differentiation. These novel findings support a model in which SMARCB1 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones, and they implicate SMARCB1 loss as a late event in tumorigenic progression. Importantly, the absence of growth inhibition after SMARCB1 restoration creates a unique opportunity to identify therapeutic vulnerabilities.
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