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Nat Commun. 2018 Feb 22;9(1):771. doi: 10.1038/s41467-018-03224-w.

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

Author information

1
Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, 20892-4258, MD, USA.
2
Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, 75 Mikras Asias St, Athens, GR-11527, Greece.
3
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, 20892-4258, MD, USA.
4
Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
5
Cancer Research UK, Cambridge Research Institute, Robinsons Way, Cambridge, CB2 0RE, UK.
6
UCL Cancer Institute, Huntley St, Camden Town, London, WC1E 6DD, UK.
7
Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou St., GR-11527, Athens, Greece.
8
Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health, Science Centre, Wilmslow Road, Manchester, M20 4QL, UK.
9
Laboratory of Human Carcinogenesis, NCI-CCR, National Institutes of Health, Bethesda, 20892-4258, MD, USA. curtis_harris@nih.gov.

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.

PMID:
29472616
PMCID:
PMC5823939
DOI:
10.1038/s41467-018-03224-w
[Indexed for MEDLINE]
Free PMC Article

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