TY - JOUR
T1 - Head and neck cancer exosomes drive microRNA-mediated reprogramming of local neurons
AU - Hunt, Patrick J.
AU - Amit, Moran
N1 - Funding Information:
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).
Publisher Copyright:
© The Author(s) 2020.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - adrenergic neurons
KW - microenvironment
KW - MicroRNA
KW - neuron-tumor crosstalk
KW - neurotrophic growth
KW - solid tumors
UR - http://www.scopus.com/inward/record.url?scp=85128187743&partnerID=8YFLogxK
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U2 - 10.20517/evcna.2020.04
DO - 10.20517/evcna.2020.04
M3 - Comment/debate
C2 - 33554224
AN - SCOPUS:85128187743
SN - 2767-6641
VL - 1
SP - 57
EP - 62
JO - Extracellular Vesicles and Circulating Nucleic Acids
JF - Extracellular Vesicles and Circulating Nucleic Acids
IS - 1
ER -