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Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246.
Cooks, T Pateras, I Jenkins, L Patel, K Robles, A Morris, J Forshew, T Appella, E Gorgoulis, Vassilis G Harris, C
Cooks, T
Pateras, I
Jenkins, L
Patel, K
Robles, A
Morris, J
Forshew, T
Appella, E
Gorgoulis, Vassilis G
Harris, C
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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.
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Date
2018
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Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. 2018, 9(1): 771 Nat Commun