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Hunt et al. Extracell Vesicles Circ Nucleic Acids 2020;1:57-62 I http://dx.doi.org/10.20517/evcna.2020.04 Page 61
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and p53 tumor cells likely contribute more to the specific release of different EV-delivered miRNAs
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than other subpopulations of p53 and p53 tumor cells. Cellular heterogeneity within tumors is
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a well-described aspect of tumor biology that affects tumor activity, and the different mutations and
transcriptional profiles found within different subpopulations may be an important driver of differential
miRNA expression and release through EVs. Modern sequencing techniques, including single-cell RNA
sequencing of tumor samples will be valuable in unraveling the link between specific transcriptional profiles
and EV-mediated miRNA delivery. Additionally, this work argues for the increased use of EV sampling
in the diagnosis, surveillance and treatment of various cancer types. Sampling EV contents from blood,
plasma, and other bodily fluids is a non-invasive and cost-effective method of providing researchers and
care teams with myriad signals and transporters shared between the tumor and the microenvironment [28–31] .
Moreover, while these contents serve as potent biomarkers of cancer presence, diagnosis, and progression,
they also provide clues as to which treatment approaches may be most effective in treating specific patients.
Stemming from this work, analysis of EV contents will also identify novel proteins and RNA messengers,
thereby identifying alternative signaling pathways, and furthering our understanding of how neuron-tumor
trophic relationships are established and sustained.

[18]
In this work, Amit et al. uncovered a novel and potent method by which OCSCC tumors manipulate
nearby sensory neurons to drive a neo-adrenergic neurotype switching event, thereby driving tumor
growth and spread. These findings constitute a paradigm shift in our understanding of how tumors
and neurons within the microenvironment interact with each other. Moreover, this work illustrates the
importance of EV contents, and more specifically, miRNA signaling in mediating the trophic relationships
between tumors and neurons that drive tumor growth. Future work will focus on further deciphering EV-
mediated signaling, with a focus on developing novel approaches of using EV analysis to better understand
tumor biology, and to better treat human cancer patients.

DECLARATIONS
Author’s contribution
PJH and MA Conceptualized the manuscript:.
PJH wrote the first draft of the manuscript. MA supplied technical knowledge to support the manuscript
throughout the revision process. PJH created the graphical abstract for the manuscript. PJH and MA
contributed to the manuscript revision and approved the submitted version.

Availability of data and materials
Not applicable.

Financial support and sponsorship
The authors would like to thank the AHA (American Heart Association Award number 20PRE35040011)
and BRASS (Baylor Research Advocates for Student Scientists) for their support (PJH). The authors would
like to thank the Moon Shots Program for their support (MA). The authors would also like to thank the
NIH/NCI for their support under award numbers P30CA016672 and 1R37CA242006 (MA).

Conflicts of interest
The authors declare no conflict of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.