Recent studies have identified tumor-derived microvesicles called exosomes as vehicles for long-distance communication, due to their complex content of proteins and microRNAs. In head and neck squamous cell carcinoma, as in many other cancers, exosome secretion is associated with advanced patient stage. In most cases, those vesicles are classified as exosomes, 50-100 nm vesicles that have been shown to mediate progression, metastasis, survival, drug resistance, immune modulation, and many other aggressive cancer phenotypes. The mechanisms by which exosomes are generated are poorly understood, although exosomes are known to derive from a late endocytic compartment. Our recent preliminary data suggest that invadopodia are sites of exosome secretion and that, conversely, canonical invadopodia regulators affect exosome secretion. Based on these and other findings, we hypothesize that exocytic late endosomal/lysosomal pathways that govern invadopodia activity and exosome secretion may be one and the same. Furthermore, these pathways are likely to be unregulated in the 30-40% of HNSCC tumors that carry amplification of the 11q13.3 amplicon, since we have shown that the 11q13-amplified cytoskeletal protein cortactin is a key regulator of invadopodia activity, exosome secretion, and tumor aggressiveness. In this project, we will test whether invadopodia represent docking sites for exosomes and identify key intracellular regulatory points for exosome secretion by HNSCC cells. We will also test the hypothesis that 11q13-amplification is an independent predictor of exosome secretion in HNSCC patients. Finally, we will determine whether inhibition of exosome secretion represents a viable therapeutic strategy in HNSCC.

Public Health Relevance

This project will study the mechanism and impact of exosome secretion in head and neck squamous cell carcinoma progression. The project is relevant to public health because it will lead to a greater understanding of mechanisms that lead to head and neck cancer aggressiveness and test whether anti-exosome targeting is a promising therapeutic option.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163592-02
Application #
8446310
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mohla, Suresh
Project Start
2012-03-19
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$304,278
Indirect Cost
$109,228
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Sinha, Seema; Hoshino, Daisuke; Hong, Nan Hyung et al. (2016) Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol 214:197-213
Siqueira, Adriane S; Pinto, Monique P; Cruz, Mário C et al. (2016) Laminin-111 peptide C16 regulates invadopodia activity of malignant cells through β1 integrin, Src and ERK 1/2. Oncotarget :
Maas, Sybren L N; Breakefield, Xandra O; Weaver, Alissa M (2016) Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol :
Wirtz, Eric D; Hoshino, Daisuke; Maldonado, Anthony T et al. (2015) Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies. JAMA Otolaryngol Head Neck Surg 141:543-9
Koshikawa, Naohiko; Hoshino, Daisuke; Taniguchi, Hiroaki et al. (2015) Proteolysis of EphA2 Converts It from a Tumor Suppressor to an Oncoprotein. Cancer Res 75:3327-39
Sung, Bong Hwan; Ketova, Tatiana; Hoshino, Daisuke et al. (2015) Directional cell movement through tissues is controlled by exosome secretion. Nat Commun 6:7164
Cleghorn, Whitney M; Branch, Kevin M; Kook, Seunghyi et al. (2015) Arrestins regulate cell spreading and motility via focal adhesion dynamics. Mol Biol Cell 26:622-35
Young, Christian D; Zimmerman, Lisa J; Hoshino, Daisuke et al. (2015) Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer. Mol Cell Proteomics 14:1959-76
Hong, Nan Hyung; Qi, Aidong; Weaver, Alissa M (2015) PI(3,5)P2 controls endosomal branched actin dynamics by regulating cortactin-actin interactions. J Cell Biol 210:753-69
Hoshino, Daisuke; Kirkbride, Kellye C; Costello, Kaitlin et al. (2013) Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep 5:1159-68

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