Mutant P53 Cancers Reprogram Macrophages to Tumor Supporting Macrophages Via Exosomal MiR-1246

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Feb 24

PMID 29472616

Citations 277

Authors

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

Affiliations

Soon will be listed here.

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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