Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.

Publication Type	Academic Article
Authors	Suresh S, Rabbie R, Garg M, Lumaquin D, Huang T, Montal E, Ma Y, Cruz N, Tang X, Nsengimana J, Newton-Bishop J, Hunter M, Zhu Y, Chen K, de Stanchina E, Adams D, White R
Journal	Cancer Discov
Volume	13
Issue	1
Pagination	194-215
Date Published	01/09/2023
ISSN	2159-8290
Keywords	Zebrafish, Melanoma
Abstract	UNLABELLED: 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. SIGNIFICANCE: 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.
DOI	10.1158/2159-8290.CD-22-0427
PubMed ID	36259947
PubMed Central ID	PMC9827116