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Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246

Author

Listed:
  • Tomer Cooks

    (National Institutes of Health)

  • Ioannis S. Pateras

    (National Kapodistrian University of Athens)

  • Lisa M. Jenkins

    (National Institutes of Health)

  • Keval M. Patel

    (Addenbrooke’s Hospital)

  • Ana I. Robles

    (National Institutes of Health)

  • James Morris

    (Cambridge Research Institute)

  • Tim Forshew

    (UCL Cancer Institute)

  • Ettore Appella

    (National Institutes of Health)

  • Vassilis G. Gorgoulis

    (National Kapodistrian University of Athens
    Biomedical Research Foundation of the Academy of Athens
    Medicine and Health, University of Manchester, Manchester Academic Health)

  • Curtis C. Harris

    (National Institutes of Health)

Abstract

TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis. Here, we report a non-cell-autonomous mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancer-promoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis.

Suggested Citation

  • Tomer Cooks & Ioannis S. Pateras & Lisa M. Jenkins & Keval M. Patel & Ana I. Robles & James Morris & Tim Forshew & Ettore Appella & Vassilis G. Gorgoulis & Curtis C. Harris, 2018. "Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03224-w
    DOI: 10.1038/s41467-018-03224-w
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