PUBLICATION
A high-content screen identifies drugs that restrict tumor cell extravasation across the endothelial barrier
- Authors
- Hilfenhaus, G., Mompeón, A., Freshman, J., Prajapati, D., Hernandez, G., Freitas, V.M., Ma, F., Langenbacher, A.D., Mirkov, S., Song, D., Cho, B.K., Goo, Y.A., Pellegrini, M., Chen, J.N., Damoiseaux, R., Iruela-Arispe, M.L.
- ID
- ZDB-PUB-201123-4
- Date
- 2020
- Source
- Cancer research 81(3): 619-633 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Communication/drug effects
- Cell Line, Tumor
- Cell Proliferation
- Colforsin/pharmacology*
- Drug Screening Assays, Antitumor/methods
- Endothelial Cells/drug effects
- Endothelium, Vascular*/drug effects
- Female
- Human Umbilical Vein Endothelial Cells
- Humans
- Kininogens/analysis
- Lung Neoplasms/pathology*
- Male
- Metabolomics
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Neoplasm Invasiveness
- Neoplastic Cells, Circulating*
- Niclosamide/pharmacology*
- Proteomics
- Transendothelial and Transepithelial Migration/drug effects*
- Zebrafish
- PubMed
- 33218969 Full text @ Cancer Res.
Citation
Hilfenhaus, G., Mompeón, A., Freshman, J., Prajapati, D., Hernandez, G., Freitas, V.M., Ma, F., Langenbacher, A.D., Mirkov, S., Song, D., Cho, B.K., Goo, Y.A., Pellegrini, M., Chen, J.N., Damoiseaux, R., Iruela-Arispe, M.L. (2020) A high-content screen identifies drugs that restrict tumor cell extravasation across the endothelial barrier. Cancer research. 81(3):619-633.
Abstract
Metastases largely rely on hematogenous dissemination of tumor cells via the vascular system and significantly limit prognosis of patients with solid tumors. To colonize distant sites, circulating tumor cells must destabilize the endothelial barrier and transmigrate across the vessel wall. Here we performed a high-content screen to identify drugs that block tumor cell extravasation by testing 3520 compounds on a transendothelial invasion co-culture assay. Hits were further characterized and validated using a series of in vitro assays, a zebrafish model enabling 3-D visualization of tumor cell extravasation, and mouse models of lung metastasis. The initial screen advanced 38 compounds as potential hits, of which 4 compounds enhanced endothelial barrier stability while concurrently suppressing tumor cell motility. Two compounds niclosamide and forskolin significantly reduced tumor cell extravasation in zebrafish, and niclosamide drastically impaired metastasis in mice. Because niclosamide had not previously been linked with effects on barrier function, single cell RNA sequencing uncovered mechanistic effects of the drug on both tumor and endothelial cells. Importantly, niclosamide affected homotypic and heterotypic signaling critical to intercellular junctions, cell-matrix interactions, and cytoskeletal regulation. Proteomic analysis indicated that niclosamide-treated mice also showed reduced levels of kininogen, the precursor to the permeability mediator bradykinin. Our findings designate niclosamide as an effective drug that restricts tumor cell extravasation through modulation of signaling pathways, chemokines, and tumor-endothelial cell interactions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping