Cited by 179Melanoma and MAPK PathwaysCancer, Lipids, and MetabolismMechanisms of cancer metastasis

Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation

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Pencheva, Nora, Buss, Colin G., Posada, Jessica, Merghoub, Taha, Tavazoie, Sohail F.·2014·Cell

Abstract

Melanoma metastasis is a devastating outcome lacking an effective preventative therapeutic. We provide pharmacologic, molecular, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Oral administration of multiple LXR agonists suppressed melanoma invasion, angiogenesis, tumor progression, and metastasis. Molecular and genetic experiments revealed these effects to be mediated by LXRβ, which elicits these outcomes through transcriptional induction of tumoral and stromal apolipoprotein-E (ApoE). LXRβ agonism robustly suppressed tumor growth and metastasis across a diverse mutational spectrum of melanoma lines. LXRβ targeting significantly prolonged animal survival, suppressed the progression of established metastases, and inhibited brain metastatic colonization. Importantly, LXRβ activation displayed melanoma-suppressive cooperativity with the frontline regimens dacarbazine, B-Raf inhibition, and the anti-CTLA-4 antibody and robustly inhibited melanomas that had acquired resistance to B-Raf inhibition or dacarbazine. We present a promising therapeutic approach that uniquely acts by transcriptionally activating a metastasis suppressor gene.

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Crossref · 10.1016/j.cell.2014.01.038

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  • Pharmacological activation of LXRβ suppresses melanoma tumor progression and metastatic colonization, effects caused by ApoE-mediated suppression of pro-metastatic invasion and endothelial recruitment phenotypes.

    “pharmacological activation of the ubiquitously expressed LXRβ isoform was found to suppress melanoma tumor progression and metastatic colonization—effects caused by ApoE-mediated suppression of pro-metastatic invasion and endothelial recruitment phenotypes”

    From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Pencheva et al., 2014

  • The anti-tumor effects of LXR agonists are mediated by LXRβ and its transcriptional target Apoe.

    “We had previously shown that the anti-tumor effects of LXR agonists were mediated by the ubiquitously expressed LXRβ nuclear hormone receptor and its transcriptional target Apoe”

    From LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer (2018) · cites this paper as Pencheva et al., 2014

  • Tumoral and stroma-derived APOE suppresses melanoma progression.

    “We previously reported that tumoral and stroma-derived APOE suppresses melanoma progression4,12,13.”
  • Both tumor-derived and stroma-derived APOE regulate melanoma metastatic capacity via extracellular action on tumoral APOE receptors.

    “APOE protein is known to act extracellularly on tumoral APOE receptors, and both tumor-derived and stroma-derived APOE have been found to regulate melanoma metastatic capacity in this manner (4,5).”
  • APOE protein acts extracellularly on tumoral APOE receptors.

    “APOE protein is known to act extracellularly on tumoral APOE receptors, and both tumor-derived and stroma-derived APOE have been found to regulate melanoma metastatic capacity in this manner (4,5).”

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Authors
Pencheva, N., Buss, C. G., Posada, J., Merghoub, T., & Tavazoie, S. F.
Affiliations
  • Rockefeller University (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Tavazoie, Sohail F.
Venue
Cell
Publisher
Elsevier BV
Published
2014-02
Volume
156
Issue
5
Pages
986-1001
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2133717967
Cited by
175
References
40
Citations by year
2026: 3 · 2025: 5 · 2024: 15 · 2023: 14 · 2022: 17 · 2021: 14 · 2020: 27 · 2019: 14 · 2018: 16 · 2017: 10 · 2016: 13 · 2015: 20 · 2014: 6
FWCI
6.70
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense
  • Rita Allen Foundation
  • Melanoma Research Alliance
  • Allen Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
metastatic melanoma, liver X receptor, apolipoprotein E, metastasis suppression, angiogenesis, brain metastases, CTLA-4 blockade, combination therapy, stromal cells, transcriptional activation
MeSH terms
Liver X Receptors, Benzenesulfonamides, Animals, Apolipoproteins E, Benzoates, Benzylamines, Cells, Cultured, Disease Models, Animal, Fluorocarbons, Humans, Hydrocarbons, Fluorinated, Melanoma, Neoplasm Metastasis, Skin Neoplasms, Sulfonamides, Transcription, Genetic, Signal Transduction, Mice, Orphan Nuclear Receptors

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