A chronic signaling TGFb zebrafish reporter identifies immune response in melanoma

Author:

Noonan Haley R1234ORCID,Thornock Alexandra M1234ORCID,Barbano Julia1,Xifaras Michael E1235,Baron Chloe S123,Yang Song123,Koczirka Katherine1,McConnell Alicia M123,Zon Leonard I123ORCID

Affiliation:

1. Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute

2. Stem Cell and Regenerative Biology Department, Harvard University

3. Harvard Medical School

4. Biological and Biomedical Sciences Program, Harvard Medical School

5. Immunology Program, Harvard Medical School

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.

Funder

National Institutes of Health

Melanoma Research Alliance

Publisher

eLife Sciences Publications, Ltd

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