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Hunt et al. Extracell Vesicles Circ Nucleic Acids 2020;1:57-62 Extracellular Vesicles and
DOI: 10.20517/evcna.2020.04 Circulating Nucleic Acids

Commentary Open Access

Head and neck cancer exosomes drive microRNA-
mediated reprogramming of local neurons

Patrick J. Hunt , Moran Amit 3
1,2
1 Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
2 Department of Neurosurgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030,
USA.
3 Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston,
TX 77030, USA.

Correspondence to: Dr. Moran Amit, MD, PhD, Department of Head and Neck Surgery, The University of Texas MD Anderson
Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: mamit@mdanderson.org

How to cite this article: Hunt PJ, Amit M. Head and neck cancer exosomes drive microRNA-mediated reprogramming of local
neurons. Extracell Vesicles Circ Nucleic Acids 2020;1:57-62. http://dx.doi.org/10.20517/evcna.2020.04

Received: 16 Dec 2020 First Decision: 24 Dec 2020 Revised: 27 Dec 2020 Accepted: 29 Dec 2020 Available online: 30 Dec 2020

Academic Editor: Y. Peng Loh Copy Editor: Huan-Liang Wu Production Editor: Jing Yu

Abstract
Solid tumors are complex collections of cells surrounded by benign tissues that influence and are influenced
by the tumor. These surrounding cells include vasculature, immune cells, neurons, and other cell types, and are
collectively known as the tumor microenvironment. Tumors manipulate their microenvironment for the benefit
of the tumor. Autonomic neurons innervate and drive malignant growth in a variety of solid tumors. However, the
mechanisms underlying neuron-tumor relationships are not well understood. Recently, Amit et al. described that
trophic relationships between oral cavity squamous cell carcinomas (OCSCCs) and nearby autonomic neurons
arise through direct signaling between tumors and local neurons. An inducible tumor model in which 4NQO
was introduced into the drinking water of Trp53 knockout mice was used to model OCSCC-microenvironment
interactions. Using this model, this group discovered that loss of p53 expression in OCSCC tumors resulted in
increased nerve density within these tumors. This neuritogenesis was controlled by tumor-derived microRNA-
laden extracellular vesicles (EVs). Specifically, EV-delivered miR-34a inhibited neuritogenesis, whereas EV-
delivered miR-21 and miR-324 increased neuritogenesis. The neurons innervating p53-deficient OCSCC tumors
were predominantly adrenergic and arose through the transdifferentiation of trigeminal sensory nerve fibers to
adrenergic nerve fibers. This transdifferentiation corresponded with increased expression of neuron-reprogramming
transcription factors, including POU5F1, KLF4, and ASCL1, which were overexpressed in the p53-deficient samples,
and are proposed targets of miR-34a-mediated regulation. Human OCSCC samples enriched in adrenergic neuron
markers are associated strongly with poor outcomes, thus demonstrating the relevance of these findings to cancer
patients.
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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