Childhood Cancer Data Initiative Annual Symposium (Abstract Registration): Submission #66

serial: '66'
sid: '190730'
uuid: 6d298f83-d0e0-4a1d-a528-b525c43c8309
uri: /nci/ccdisymposium/abstract
created: '1786554052'
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data:
  authors_:
    - add_author_degree: Ph.D
      add_author_first_name: Janice
      add_author_last_name: Pereira
      add_author_middle: S
      add_author_organization: 'NCI, NIH'
    - add_author_degree: Ph.D
      add_author_first_name: Lauren
      add_author_last_name: McGee
      add_author_middle: E
      add_author_organization: 'NCI, NIH'
    - add_author_degree: Ph.D
      add_author_first_name: Anjali
      add_author_last_name: Garg
      add_author_middle: ''
      add_author_organization: 'NCI, NIH'
    - add_author_degree: BS
      add_author_first_name: Kate
      add_author_last_name: Silver
      add_author_middle: I
      add_author_organization: 'NCI, NIH'
    - add_author_degree: Ph.D
      add_author_first_name: Troy
      add_author_last_name: McEachron
      add_author_middle: A
      add_author_organization: 'NCI, NIH'
    - add_author_degree: BS
      add_author_first_name: Christina
      add_author_last_name: Mazcko
      add_author_middle: ''
      add_author_organization: 'NCI, NIH'
    - add_author_degree: 'DVM Ph.D DACVP'
      add_author_first_name: Jessica
      add_author_last_name: Beck
      add_author_middle: A
      add_author_organization: 'NCI, NIH and OSU'
    - add_author_degree: DVM
      add_author_first_name: Amy
      add_author_last_name: LeBlanc
      add_author_middle: K
      add_author_organization: 'NCi, NIH'
  abstract: 'Pulmonary metastasis is the leading cause of mortality in human and canine osteosarcoma (OS) patients, yet the contribution of lung-resident type II pneumocytes (TIIPs) to metastatic progression is under-defined. This study characterizes the distribution of pneumocytes in the OS lung metastasis microenvironment, defines the consequences of TIIP-OS crosstalk, and identifies a therapeutic strategy to limit pulmonary metastatic progression. Spatial transcriptomics and complementary IHC staining of human, canine, and murine OS lung metastases showed increased TIIP accumulation at the tumor:non-tumor interface compared to distal lung parenchyma. Indirect co-culture of human primary TIIPs with MG63.2 OS cells significantly increased tumor cell proliferation, an effect reproduced with TIIP-conditioned media, suggesting that soluble TIIP-derived factors are pro-tumorigenic. RNA sequencing of co-cultured TIIPs showed enrichment of the p53 pathway, consistent with an injury/stress response resembling idiopathic pulmonary fibrosis. Cytokine profiling and Enrichr pathway analysis identified a pro-fibrotic secretome as a dominant feature of TIIP-OS crosstalk. Targeting TGF-β-mediated fibrosis with a dual integrin inhibitor reduced K7M2 OS proliferation in TIIP co-culture but not in monoculture, suggesting that the anti-proliferative effect is mediated through disruption of TIIP-OS crosstalk. A K7M2-pEGFP experimental metastasis model treated with 5 mg/kg or 25 mg/kg inhibitor showed significant dose-dependent reductions in metastases versus vehicle control. These findings provide the first cross-species characterization of TIIP spatial distribution within the OS pulmonary metastatic niche, demonstrating that TIIPs establish a growth-permissive, pro-fibrotic crosstalk with tumor cells. Disrupting this crosstalk represents a promising therapeutic strategy to limit metastatic progression and improve survival outcomes for OS patients.'
  abstract_title_: 'Repurposing Anti-Fibrotic Strategies to Target Type II Pneumocyte-Driven Osteosarcoma Metastatic Progression'
  email_address_: janice.pereira@nih.gov
  institution_: 'NCI, NIH'
  presenting_author_: 'Janice S. Pereira'