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Verteporfin targets CCR5 to inhibit TNBC growth and metastasis via YAP1

ABSTRACT: CCL5/CCR5 axis is an immunotherapeutic target for triple-negative breast cancer (TNBC). However, the signaling mechanism is poorly understood and its antagonists have not been reported. Here, we developed a high-throughput screening (HTS) assay for discovering its antagonists. Verteporfin was identified as a specific and more potent inhibitor than maraviroc. It significantly reduced TNBC tumor growth in an immunologically dependent manner, and lung metastasis in a cell-intrinsic way. Mechanistically, CCR5 was co-expressed with Yes-associated protein 1 (YAP1) in TNBC patients. RNA-sequencing and expression silencing further revealed that CCR5 promoted the expression of YAP1 through HIF-1α in TNBC cells, and through YAP1 to regulate β-catenin, ZEB1/ZEB2 for metastasis, as well as CXCL16 and CXCL8 for immune cell migration and tumor growth. In essence, verteporfin may have potential immunotherapeutic applications for diseases co-expressing CCR5 and YAP1 such as TNBC. The HTS assay can be adapted for unveiling antagonists of broader signaling pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222052 | GEO | 2024/01/25

REPOSITORIES: GEO

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