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Activation of NFAT by HGF and IGF-1 via ARF6 and its effector ASAP1 promotes uveal melanoma metastasis

Oncogene volume 42, pages 2629–2640 (2023)Cite this article

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A Correction to this article was published on 08 September 2023

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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.

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Fig. 1: ARF6 is hyperactivated by HGF and IGF-1 and promotes invasion of uveal melanoma cells.
Fig. 2: ASAP1 is required for invasion and metastasis of uveal melanoma.
Fig. 3: Activated ARF6 increases NFAT1 nuclear localization and transcriptional activity.
Fig. 4: Activated ARF6 and ASAP1 are required for both IGF-1- and HGF-induced NFAT1 nuclear localization and transcriptional activity.
Fig. 5: Calcineurin and NFAT inhibitors reduce invasion of uveal melanoma cells.
Fig. 6: Inhibition of NFAT reduces metastasis in vivo.

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All data that support the results of this study can be found within the main text and figures of this paper or in the Supplementary information.

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Acknowledgements

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.

Funding

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).

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Author notes

  1. Jackson R. Richards

    Present address: Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

  2. These authors contributed equally: Shannon J. Odelberg, Jae Hyuk Yoo.

Authors and Affiliations

  1. Department of Oncological Sciences, School of Medicine, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA

    Jackson R. Richards, Amanda Truong & Martin McMahon

  2. Department of Medicine, Program in Molecular Medicine, University of Utah, 15 North 2030 East, Salt Lake City, UT, 84112, USA

    Jackson R. Richards, Donghan Shin, Rob Pryor, Lise K. Sorensen, Zhonglou Sun, Weiquan Zhu & Shannon J. Odelberg

  3. Department of Ophthalmology & Visual Sciences, Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Won Mi So, Garam Park & Jae Hyuk Yoo

  4. Department of Pathology, University of Utah, 15 North Medical Drive East, Salt Lake City, UT, 84112, USA

    Roger Wolff & Allie H. Grossmann

  5. Huntsman Cancer Institute, University of Utah Health Sciences Center, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA

    Roger Wolff, Amanda Truong, Martin McMahon & Allie H. Grossmann

  6. Department of Dermatology, University of Utah, 30 N 1900 E, Salt Lake City, UT, 84132, USA

    Martin McMahon

  7. ARUP Laboratories, University of Utah, 500 Chipeta Way, Salt Lake City, UT, 84112, USA

    Allie H. Grossmann

  8. Department of Ophthalmology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    J. William Harbour

  9. Division of Cardiovascular Medicine, Department of Medicine, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA

    Weiquan Zhu & Shannon J. Odelberg

  10. Department of Neurobiology, University of Utah, 20 South 2030 East, Salt Lake City, UT, 84112, USA

    Shannon J. Odelberg

  11. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Jae Hyuk Yoo

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Contributions

SJO and JHY were responsible for conceptualization, experimental design, data analysis, and manuscript preparation. JHY primarily performed and collected data for in vitro experiments. JRR and DS primarily performed and collected data for in vivo experiments. RP, ZS, WMS, GP, and AT performed in vitro/in vivo experiments. LKS performed immunocytofluorescent staining. RW performed bioinformatic analyses. AHG provided histology and pathology expertise. MM, AHG, JWH, and WZ provided resources and critical review of the manuscript. All authors read the manuscript, agree with the content, and were given the opportunity to provide input.

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Correspondence to Shannon J. Odelberg or Jae Hyuk Yoo.

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Competing interests

JWH is the inventor of intellectual property related to prognostic testing in uveal melanoma. He is a paid consultant for Castle Biosciences, licensee of this intellectual property, and he receives royalties from its commercialization.

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Richards, J.R., Shin, D., Pryor, R. et al. Activation of NFAT by HGF and IGF-1 via ARF6 and its effector ASAP1 promotes uveal melanoma metastasis. Oncogene 42, 2629–2640 (2023). https://doi.org/10.1038/s41388-023-02792-6

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