Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Sabine Heitzeneder, Stanford University
  • ,
  • Elena Sotillo, Stanford University
  • ,
  • Jack F. Shern, NIH, National Institutes of Health (NIH) - USA, NIH National Cancer Institute (NCI), Pediat Oncol Branch, Natl Canc Ctr
  • ,
  • Sivasish Sindiri, NIH, National Institutes of Health (NIH) - USA, NIH National Cancer Institute (NCI), Canc Genet Branch, Natl Canc Ctr
  • ,
  • Peng Xu, Stanford University
  • ,
  • Robert Jones, Stanford University
  • ,
  • Michael Pollak, McGill Univ, McGill University, Dept Oncol, SMBD Jewish Gen Hosp, Lady Davis Inst,Dept Expt Med
  • ,
  • Pernille R. Noer
  • Julie Lorette, Univ British Columbia, University of British Columbia, Dept Pathol & Lab Med
  • ,
  • Ladan Fazli, Univ British Columbia, University of British Columbia, Vancouver Prostate Ctr
  • ,
  • Anya Alag, Univ Calif Los Angeles, University of California Los Angeles, University of California System, Dept Phys & Astron
  • ,
  • Paul Meltzer, NIH, National Institutes of Health (NIH) - USA, NIH National Cancer Institute (NCI), Canc Genet Branch, Natl Canc Ctr
  • ,
  • Ching Lau, Jackson Lab Genom Med
  • ,
  • Cheryl A. Conover, Mayo Clin, Mayo Clinic, Endocrine Res Unit
  • ,
  • Claus Oxvig
  • Poul H. Sorensen, Univ British Columbia, University of British Columbia, Dept Pathol & Lab Med
  • ,
  • John M. Maris, Univ Penn, University of Pennsylvania, Perelman Sch Med, Dept Neurol
  • ,
  • Javed Khan, NIH, National Institutes of Health (NIH) - USA, NIH National Cancer Institute (NCI), Canc Genet Branch, Natl Canc Ctr
  • ,
  • Crystal L. Mackall, Stanford University

Background: Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulin like growth factor (IGF) signaling.

Methods: By comparing RNA expression of cell surface proteins in EWS (n = 120) versus normal tissues (n = 42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n = 5) and controls (n = 3). All statistical tests were two-sided.

Results: EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm(2) at day 49 IgG2a control (CTRL) [n = 14], mean = 397.0, SD = 86.1 vs anti-PAPP-A [n = 14], mean = 311.7, SD = 155.0; P = .03; median OS anti-PAPP-A = 52.5 days, 95% CI = 46.0 to 63.0 days vs IgG2a = 45.0 days, 95% CI = 42.0 to 52.0 days; P = .02) and improved the efficacy of anti-IGF-1R treatment (leg area mm(2) at day 49 anti-PAPP-A + anti-IGF-1R [n = 15], mean = 217.9, SD = 148.5 vs IgG2a-CTRL; P

Conclusion: This work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.

Original languageEnglish
Article number209
JournalJournal of the National Cancer Institute
Volume111
Issue9
Pages (from-to)970-982
Number of pages13
ISSN0027-8874
DOIs
Publication statusPublished - Sep 2019

    Research areas

  • FACTOR-I RECEPTOR, PROTEOLYTIC ACTIVITY, PHASE-II, CANCER, CELLS, INHIBITION, ANTIBODY, HETEROGENEITY, MECHANISMS, EXPRESSION

See relations at Aarhus University Citationformats

ID: 189815921