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Supplementary Figure S8 from Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma

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posted on 2023-04-04, 00:21 authored by Shruthy Suresh, Roy Rabbie, Manik Garg, Dianne Lumaquin, Ting-Hsiang Huang, Emily Montal, Yilun Ma, Nelly M Cruz, Xinran Tang, Jérémie Nsengimana, Julia Newton-Bishop, Miranda V. Hunter, Yuxin Zhu, Kevin Chen, Elisa de Stanchina, David J. Adams, Richard M. White

Cholesterol overload activates AP-1 via ERK signaling to mediate invasion upon GRAMD1B loss in melanoma.

Funding

Melanoma Research Foundation (MRF)

National Institutes of Health (NIH)

Wellcome Trust (WT)

Cancer Research UK (CRUK)

European Molecular Biology Laboratory (EMBL)

Swim Across America (SAA)

Melanoma Research Alliance (MRA)

Pershing Square Sohn Cancer Research Alliance (PSSCRA)

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

American Cancer Society (ACS)

Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)

Parker Institute for Cancer Immunotherapy (Parker Institute)

Debra and Leon Black Family Foundation (Leon Black Family Foundation)

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ARTICLE ABSTRACT

In melanoma, predicting which tumors will ultimately metastasize guides treatment decisions. Transcriptional signatures of primary tumors have been utilized to predict metastasis, but which among these are driver or passenger events remains unclear. We used data from the adjuvant AVAST-M trial to identify a predictive gene signature in localized tumors that ultimately metastasized. Using a zebrafish model of primary melanoma, we interrogated the top genes from the AVAST-M signature in vivo. This identified GRAMD1B, a cholesterol transfer protein, as a bona fide metastasis suppressor, with a majority of knockout animals rapidly developing metastasis. Mechanistically, excess free cholesterol or its metabolite 27-hydroxycholesterol promotes invasiveness via activation of an AP-1 program, which is associated with increased metastasis in humans. Our data demonstrate that the transcriptional seeds of metastasis are embedded within localized tumors, suggesting that early targeting of these programs can be used to prevent metastatic relapse. We analyzed human melanoma transcriptomics data to identify a gene signature predictive of metastasis. To rapidly test clinical signatures, we built a genetic metastasis platform in adult zebrafish and identified GRAMD1B as a suppressor of melanoma metastasis. GRAMD1B-associated cholesterol overload activates an AP-1 program to promote melanoma invasion.This article is highlighted in the In This Issue feature, p. 1

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    cancer

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