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 Zinger, Ennio Tasciotti, Patrick M. Dougherty, Adel El-Naggar, George A. Calin () and Jeffrey N. Myers ()
Additional contact information
Moran Amit: The University of Texas MD Anderson Cancer Center
Hideaki Takahashi: The University of Texas MD Anderson Cancer Center
Mihnea Paul Dragomir: The University of Texas MD Anderson Cancer Center
Antje Lindemann: The University of Texas MD Anderson Cancer Center
Frederico O. Gleber-Netto: The University of Texas MD Anderson Cancer Center
Curtis R. Pickering: The University of Texas MD Anderson Cancer Center
Simone Anfossi: The University of Texas MD Anderson Cancer Center
Abdullah A. Osman: The University of Texas MD Anderson Cancer Center
Yu Cai: The University of Texas MD Anderson Cancer Center
Rong Wang: The University of Texas MD Anderson Cancer Center
Erik Knutsen: The University of Texas MD Anderson Cancer Center
Masayoshi Shimizu: The University of Texas MD Anderson Cancer Center
Cristina Ivan: The University of Texas MD Anderson Cancer Center
Xiayu Rao: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Deborah A. Silverman: The University of Texas MD Anderson Cancer Center
Samantha Tam: The University of Texas MD Anderson Cancer Center
Mei Zhao: The University of Texas MD Anderson Cancer Center
Carlos Caulin: University of Arizona
Assaf Zinger: Houston Methodist Research Institute
Ennio Tasciotti: Houston Methodist Research Institute
Patrick M. Dougherty: The University of Texas MD Anderson Cancer Center
Adel El-Naggar: The University of Texas MD Anderson Cancer Center
George A. Calin: The University of Texas MD Anderson Cancer Center
Jeffrey N. Myers: The University of Texas MD Anderson Cancer Center

Nature, 2020, vol. 578, issue 7795, 449-454

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-1996-3

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