PUBLICATION
Identifying the transcriptional drivers of metastasis embedded within localized melanoma
- Authors
- Suresh, S., Rabbie, R., Garg, M., Lumaquin, D., Huang, T.H., Montal, E., Ma, Y., Cruz, N.M., Tang, X., Nsengimana, J., Newton-Bishop, J., Hunter, M.V., Zhu, Y., Chen, K., de Stanchina, E., Adams, D.J., White, R.M.
- ID
- ZDB-PUB-221020-4
- Date
- 2022
- Source
- Cancer discovery 13(1): 194-215 (Journal)
- Registered Authors
- White, Richard M.
- Keywords
- none
- MeSH Terms
-
- Animals
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Melanoma*/pathology
- Neoplasm Metastasis
- Neoplasm Recurrence, Local/genetics
- Transcription Factor AP-1/genetics
- Transcription Factor AP-1/metabolism
- Zebrafish*/genetics
- PubMed
- 36259947 Full text @ Cancer Discov
Citation
Suresh, S., Rabbie, R., Garg, M., Lumaquin, D., Huang, T.H., Montal, E., Ma, Y., Cruz, N.M., Tang, X., Nsengimana, J., Newton-Bishop, J., Hunter, M.V., Zhu, Y., Chen, K., de Stanchina, E., Adams, D.J., White, R.M. (2022) Identifying the transcriptional drivers of metastasis embedded within localized melanoma. Cancer discovery. 13(1):194-215.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping