Loss of p53 drives neuron reprogramming in head and neck cancer

Moran Amit, Hideaki Takahashi, Mihnea Paul Dragomir, Antje Lindemann, Frederico O. Gleber-Netto, Curtis R. Pickering, Simone Anfossi, Abdullah A. Osman, Yu Cai, Rong Wang, Erik Knutsen, Masayoshi Shimizu, Cristina Ivan, Xiayu Rao, Jing Wang, Deborah A. Silverman, Samantha Tam, Mei Zhao, Carlos Caulin, Assaf ZingerEnnio Tasciotti, Patrick M. Dougherty, Adel El-Naggar, George A. Calin, Jeffrey N. Myers

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system1,2. 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 unknown1,3. 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.

Original languageEnglish (US)
Pages (from-to)449-454
Number of pages6
JournalNature
Volume578
Issue number7795
DOIs
StatePublished - Feb 20 2020

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Loss of p53 drives neuron reprogramming in head and neck cancer'. Together they form a unique fingerprint.

Cite this