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

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.

• Authors: 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, Jeffrey N Myers
• Journal: Nature (Nature) Vol. 578 Issue 7795 Pg. 449-454 (02 2020) ISSN: 1476-4687 [Electronic] England
• PMID: 32051587 (Publication Type: Journal Article)

Chemical References

• Adrenergic Antagonists
• MIRN34 microRNA, human
• MicroRNAs
• Receptors, Adrenergic
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Adrenergic Antagonists (pharmacology, therapeutic use)
• Adrenergic Neurons (pathology)
• Animals
• Cell Division
• Cell Transdifferentiation
• Cellular Reprogramming
• Disease Models, Animal
• Disease Progression
• Female
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• MicroRNAs (genetics)
• Mouth Neoplasms (drug therapy, genetics, metabolism, pathology)
• Nerve Fibers (pathology)
• Neurites (pathology)
• Receptors, Adrenergic (metabolism)
• Retrospective Studies
• Sensory Receptor Cells (pathology)
• Tumor Microenvironment
• Tumor Suppressor Protein p53 (deficiency, genetics)
• Xenograft Model Antitumor Assays