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 - Funding Information:
Acknowledgements G.A.C. is the Felix L. Haas Endowed Professor in Basic Science. Work in the Calin laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), NCI grants 1R01CA182905-01 and 1R01CA222007-01A1, National Institute of General Medical Sciences (NIGMS) grant 1R01GM122775-01, U54 grant CA096297/CA096300 – UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, US Department of Defense grant CA160445P1, a Chronic Lymphocytic Leukemia Moonshot Flagship Project, a Sister Institution Network Fund (SINF) 2017 grant, and the Estate of C. G. Johnson Jr. Work in the Dougherty laboratory is supported by NIH grant CA200263, Thompson Family Foundation Initiative; P.M.D. is the H.E.B. Endowed Professor in Basic Science. The NIH Cancer Center Support Grant P30CA016672 supports the High Resolution Electron Microscopy Facility (K. Dunner Jr) and the Advanced Technology Genomics Core (core grant CA016672) at The University of Texas MD Anderson Cancer Center. We thank M. Sushnitha for assistance with miRNA encapsulation; A. Patel for technical assistance; J. K. Burks for discussions and technical assistance with image analysis; C. M. Johnston; H. Kimhi; S. J. Bronson; E. Kimhi and D. M. Aten for artistic work; and our patients and their families. This work was supported by National Institute of Dental and Craniofacial Research grant 5R01 DE014613 12 (J.N.M.) and by S.I.A. funds (G.A.C.). Y.C. and R.W. were funded by the National Natural Science Foundation of China (NSFC, 81741082). D.A.S. is supported by NCI fellowship NIH/NCI F30CA228258.
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 -