@article{d4a0586456324fc388339718c64dec39,
title = "Activation of NFAT by HGF and IGF-1 via ARF6 and its effector ASAP1 promotes uveal melanoma metastasis",
abstract = "Preventing or effectively treating metastatic uveal melanoma (UM) is critical because it occurs in about half of patients and confers a very poor prognosis. There is emerging evidence that hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF-1) promote metastasis and contribute to the striking metastatic hepatotropism observed in UM metastasis. However, the molecular mechanisms by which HGF and IGF-1 promote UM liver metastasis have not been elucidated. ASAP1, which acts as an effector for the small GTPase ARF6, is highly expressed in the subset of uveal melanomas most likely to metastasize. Here, we found that HGF and IGF-1 hyperactivate ARF6, leading to its interaction with ASAP1, which then acts as an effector to induce nuclear localization and transcriptional activity of NFAT1. Inhibition of any component of this pathway impairs cellular invasiveness. Additionally, knocking down ASAP1 or inhibiting NFAT signaling reduces metastasis in a xenograft mouse model of UM. The discovery of this signaling pathway represents not only an advancement in our understanding of the biology of uveal melanoma metastasis but also identifies a novel pathway that could be targeted to treat or prevent metastatic uveal melanoma.",
author = "Richards, {Jackson R.} and Donghan Shin and Rob Pryor and Sorensen, {Lise K.} and Zhonglou Sun and So, {Won Mi} and Garam Park and Roger Wolff and Amanda Truong and Martin McMahon and Grossmann, {Allie H.} and Harbour, {J. William} and Weiquan Zhu and Odelberg, {Shannon J.} and Yoo, {Jae Hyuk}",
note = "Funding Information: This study was supported by the National Cancer Institute R00CA230312 (JHY), the Department of Defense Melanoma Research Program ME190288 (JHY), the Melanoma Research Foundation 51005681 (JHY), the National Institute of General Medical Sciences COBRE P20GM121316 (JHY), F30CA217184 (JRR), F30CA235964 (AT) and R01CA202778 (SJO). Funding Information: We thank D. Lim for graphics preparation. This research utilized both University of Utah and Huntsman Cancer Institute shared research resources including the Preclinical Research Resource, DNA Sequencing Core Facility, Bioinformatics Core Facility, and Fluorescence Microscopy Core Facility and was supported in part by the National Cancer Institute of the National Institutes of Health under Award Number P30CA042014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2023",
month = aug,
day = "25",
doi = "10.1038/s41388-023-02792-6",
language = "English (US)",
volume = "42",
pages = "2629--2640",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "35",
}