TY - JOUR
T1 - Loss of p53 drives neuron reprogramming in head and neck cancer
AU - Amit, Moran
AU - Takahashi, Hideaki
AU - Dragomir, Mihnea Paul
AU - Lindemann, Antje
AU - Gleber-Netto, Frederico O.
AU - Pickering, Curtis R.
AU - Anfossi, Simone
AU - Osman, Abdullah A.
AU - Cai, Yu
AU - Wang, Rong
AU - Knutsen, Erik
AU - Shimizu, Masayoshi
AU - Ivan, Cristina
AU - Rao, Xiayu
AU - Wang, Jing
AU - Silverman, Deborah A.
AU - Tam, Samantha
AU - Zhao, Mei
AU - Caulin, Carlos
AU - Zinger, Assaf
AU - Tasciotti, Ennio
AU - Dougherty, Patrick M.
AU - El-Naggar, Adel
AU - Calin, George A.
AU - Myers, Jeffrey N.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/2/20
Y1 - 2020/2/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85079719323&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079719323&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-1996-3
DO - 10.1038/s41586-020-1996-3
M3 - Article
C2 - 32051587
AN - SCOPUS:85079719323
SN - 0028-0836
VL - 578
SP - 449
EP - 454
JO - Nature
JF - Nature
IS - 7795
ER -