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

Nature Communications
Tomer CooksC C Harris

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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Datasets Mentioned

BETA
GSE44861
GSE107870
MSV000082047

Methods Mentioned

BETA
ELISA
flow cytometry
transmission electron microscopy
chips
xenograft
xenografts
Amplicon Deep Sequencing
pull down
pulled down
co-immunoprecipitation

Software Mentioned

Partek Genomics Suite
Zen light
Graphpad
Proteome Discoverer
Prism
nSolver analysis
SequestHT
MSAmanda
CellQuest Pro
FlowJo

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