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Loss of p53 drives neuron reprogramming in head and neck cancer.
- 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.
- Subjects :
- Adrenergic Antagonists pharmacology
Adrenergic Antagonists therapeutic use
Animals
Cell Division
Disease Models, Animal
Disease Progression
Female
Humans
Male
Mice
Mice, Inbred BALB C
MicroRNAs genetics
Mouth Neoplasms drug therapy
Mouth Neoplasms genetics
Mouth Neoplasms metabolism
Nerve Fibers pathology
Neurites pathology
Receptors, Adrenergic metabolism
Retrospective Studies
Tumor Microenvironment
Tumor Suppressor Protein p53 genetics
Xenograft Model Antitumor Assays
Adrenergic Neurons pathology
Cell Transdifferentiation
Cellular Reprogramming
Mouth Neoplasms pathology
Sensory Receptor Cells pathology
Tumor Suppressor Protein p53 deficiency
Subjects
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