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 and Curtis C. Harris ()
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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
Curtis C. Harris: National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03224-w

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