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

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

Research output: Contribution to journalArticlepeer-review

242 Scopus citations

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.

Original languageEnglish
Article number771
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)

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