PUBLICATION
A chronic signaling TGFb zebrafish reporter identifies immune response in melanoma
- Authors
- Noonan, H.R., Thornock, A.M., Barbano, J., Xifaras, M.E., Baron, C.S., Yang, S., Koczirka, K., McConnell, A.M., Zon, L.I.
- ID
- ZDB-PUB-240615-4
- Date
- 2024
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Zon, Leonard I.
- Keywords
- TGFb, cancer biology, human, macrophages, melanoma, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified*
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic
- Genes, Reporter
- Green Fluorescent Proteins/genetics
- Green Fluorescent Proteins/metabolism
- Humans
- Melanoma*/genetics
- Melanoma*/immunology
- Melanoma*/metabolism
- Melanoma*/pathology
- Signal Transduction*
- Transforming Growth Factor beta/metabolism
- Transforming Growth Factor beta1/metabolism
- Zebrafish*
- PubMed
- 38874379 Full text @ Elife
Citation
Noonan, H.R., Thornock, A.M., Barbano, J., Xifaras, M.E., Baron, C.S., Yang, S., Koczirka, K., McConnell, A.M., Zon, L.I. (2024) A chronic signaling TGFb zebrafish reporter identifies immune response in melanoma. eLIFE. 13:.
Abstract
Developmental signaling pathways associated with growth factors such as TGFb are commonly dysregulated in melanoma. Here we identified a human TGFb enhancer specifically activated in melanoma cells treated with TGFB1 ligand. We generated stable transgenic zebrafish with this TGFb Induced Enhancer driving green fluorescent protein (TIE:EGFP). TIE:EGFP was not expressed in normal melanocytes or early melanomas but was expressed in spatially distinct regions of advanced melanomas. Single-cell RNA-sequencing revealed that TIE:EGFP+ melanoma cells down-regulated interferon response while up-regulating a novel set of chronic TGFb target genes. ChIP-sequencing demonstrated that AP-1 factor binding is required for activation of chronic TGFb response. Overexpression of SATB2, a chromatin remodeler associated with tumor spreading, showed activation of TGFb signaling in early melanomas. Confocal imaging and flow cytometric analysis showed that macrophages localize to TIE:EGFP+ regions and preferentially phagocytose TIE:EGFP+ melanoma cells compared to TIE:EGFP- melanoma cells. This work identifies a TGFb induced immune response and demonstrates the need for the development of chronic TGFb biomarkers to predict patient response to TGFb inhibitors.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping