Page 60 - Read Online

Page 56 Extracell Vesicles Circ Nucleic Acids 2020;1:20-56 I http://dx.doi.org/10.20517/evcna.2020.10

pre-miRNA processing within shed vesicles. These findings offer cellular targets to block the loading and
processing of pre-miRNAs within TMVs. As with the exosomes, it is possible that as we continue to clarify
the heterogeneity of microvesicle populations we will similarly decode additional mechanisms of miRNA
sorting to microvesicles.

REFERENCES
1. Clancy, J.W., Zhang, Y., Sheehan, C. et al. An ARF6 - Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles. Nat Cell Biol
2019; 21:856-66.

48. Head and Neck Cancer Exosomes Drive MicroRNA-mediated Reprogramming of Local
Neurons

1,2
Authors: Patrick J. Hunt , Moran Amit 3
E-mail: MAmit@MDAnderson.org
Affiliations:
1 Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
2 Department of Neurosurgery, Division of Surgery, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA.
3 Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.

Abstracts: Solid tumors are complex collections of cells surrounded by benign tissues that both influence
and are influenced by the tumor. These surrounding cells include vasculature, immune cells, neurons,
and other cell types that 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 by which these neuron-tumor relationships
are formed have not been 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 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 in cancer patients.