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Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.

ABSTRACT: Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites.

SUBMITTER: Paraiso KH

PROVIDER: S-EPMC4355213 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.

Paraiso Kim H T KH Das Thakur Meghna M Fang Bin B Koomen John M JM Fedorenko Inna V IV John Jobin K JK Tsao Hensin H Flaherty Keith T KT Sondak Vernon K VK Messina Jane L JL Pasquale Elena B EB Villagra Alejandro A Rao Uma N UN Kirkwood John M JM Meier Friedegund F Sloot Sarah S Gibney Geoffrey T GT Stuart Darrin D Tawbi Hussein H Smalley Keiran S M KS Smalley Keiran S M KS

Cancer discovery 20141226 3

<h4>Unlabelled</h4>Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry-based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inh ...[more]

PMID: 25542447

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Project description:Rationale: Angiogenesis is a fundamental process of tumorigenesis, growth, invasion and metastatic spread. Extracellular vesicles, especially exosomes, released by primary tumors promote angiogenesis and cancer progression. However, the mechanism underlying the pro-angiogenic potency of cancer cell-derived exosomes remains poorly understood. Methods: Exosomes were isolated from breast cancer cells with high metastatic potential (HM) and low metastatic potential (LM). The pro-angiogenic effects of these exosomes were evaluated by in vitro tube formation assays, wound healing assays, rat arterial ring budding assays and in vivo Matrigel plug assays. Subsequently, RNA sequencing, shRNA-mediated gene knockdown, overexpression of different EPHA2 mutants, and small-molecule inhibitors were used to analyze the angiogenesis-promoting effect of exosomal EPHA2 and its potential downstream mechanism. Finally, xenograft tumor models were established using tumor cells expressing different levels of EPHA2 to mimic the secretion of exosomes by tumor cells in vivo, and the metastasis of cancer cells were monitored using the IVIS Spectrum imaging system and Computed Tomography. Results: Herein, we demonstrated that exosomes produced by HM breast cancer cells can promote angiogenesis and metastasis. EPHA2 was rich in HM-derived exosomes and conferred the pro-angiogenic effect. Exosomal EPHA2 can be transferred from HM breast cancer cells to endothelial cells. Moreover, it can stimulate the migration and tube-forming abilities of endothelial cells in vitro and promote angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal EPHA2 activates the AMPK signaling via the ligand Ephrin A1-dependent canonical forward signaling pathway. Moreover, inhibition of the AMPK signaling impairs exosomal EPHA2-mediated pro-angiogenic effects. Conclusion: Our findings identify a novel mechanism of exosomal EPHA2-mediated intercellular communication from breast cancer cells to endothelial cells in the tumor microenvironment to provoke angiogenesis and metastasis. Targeting the exosomal EPHA2-AMPK signaling may serve as a potential strategy for breast cancer therapy.

Dataset Information

Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.

Publications

Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype.

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