Loss of p53 drives neuron reprogramming in head and neck cancer

• Published in: Nature (London) Vol. 578; no. 7795; pp. 449 - 454
• Main Authors: Amit, Moran, Takahashi, Hideaki, Dragomir, Mihnea Paul, Lindemann, Antje, Gleber-Netto, Frederico O., Pickering, Curtis R., Anfossi, Simone, Osman, Abdullah A., Cai, Yu, Wang, Rong, Knutsen, Erik, Shimizu, Masayoshi, Ivan, Cristina, Rao, Xiayu, Wang, Jing, Silverman, Deborah A., Tam, Samantha, Zhao, Mei, Caulin, Carlos, Zinger, Assaf, Tasciotti, Ennio, Dougherty, Patrick M., El-Naggar, Adel, Calin, George A., Myers, Jeffrey N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.02.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/51; 631/378/368/2431; 631/67/327; 692/699/67; Adrenergic Antagonists - pharmacology; Adrenergic Antagonists - therapeutic use; Adrenergic nerves; Adrenergic Neurons - pathology; Adrenergic receptors; Analysis; Animal models; Animals; Cell Division; Cell Transdifferentiation; Cellular Reprogramming; Control; Crosstalk; Denervation; Diagnosis; Disease Models, Animal; Disease Progression; Female; Fibers; Head & neck cancer; Head and neck cancer; Humanities and Social Sciences; Humans; Influence; Male; Mice; Mice, Inbred BALB C; MicroRNAs; MicroRNAs - genetics; miRNA; Mouth Neoplasms - drug therapy; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; multidisciplinary; Mutation; Nerve Fibers - pathology; Nerves; Neurites - pathology; Neurons; Nuclear reprogramming; Oral cancer; Organic chemistry; p53 Protein; Phenotypes; Physiological aspects; Principal components analysis; Receptors; Receptors (physiology); Receptors, Adrenergic - metabolism; Retrospective Studies; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sensory neurons; Sensory Receptor Cells - pathology; Solid tumors; Sympathetic nervous system; Tumor Microenvironment; Tumor proteins; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-1996-3

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system 1 , 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 unknown 1 , 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. MicroRNAs from head and neck cancer cells, shuttled to sensory neurons by extracellular vesicles, cause a shift to an adrenergic neuronal phenotype that promotes tumour progression.