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Loss of p53 drives neuron reprogramming in head and neck cancer.

Authors :
Amit M
Takahashi H
Dragomir MP
Lindemann A
Gleber-Netto FO
Pickering CR
Anfossi S
Osman AA
Cai Y
Wang R
Knutsen E
Shimizu M
Ivan C
Rao X
Wang J
Silverman DA
Tam S
Zhao M
Caulin C
Zinger A
Tasciotti E
Dougherty PM
El-Naggar A
Calin GA
Myers JN
Source :
Nature [Nature] 2020 Feb; Vol. 578 (7795), pp. 449-454. Date of Electronic Publication: 2020 Feb 12.
Publication Year :
2020

Abstract

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system <superscript>1,2</superscript> . Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown <superscript>1,3</superscript> . Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.

Details

Language :
English
ISSN :
1476-4687
Volume :
578
Issue :
7795
Database :
MEDLINE
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
32051587
Full Text :
https://doi.org/10.1038/s41586-020-1996-3