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PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma
M Imran Aslam1, Jinu Abraham, Atiya Mansoor
1Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239.
Abstract:
Alveolar rhabdomyosarcoma (aRMS) is an aggressive myogenic childhood malignancy, not infrequently presenting as incurable metastatic disease. To identify therapeutic targets, we performed an unbiased tyrosine kinome RNA interference screen in primary cell cultures from a genetically engineered, conditional mouse model of aRMS. We identified ephrin receptor B4 (EphB4) as a target that is widely expressed in human aRMS and that portends a poor clinical outcome in an expression level-dependent manner. We also uncovered cross-talk of this ephrin receptor with another receptor tyrosine kinase, PDGFRβ, which facilitates PDGF ligand-dependent, ephrin ligand-independent activation of EphB4 converging on the Akt and Erk1/2 pathways. Conversely, EphB4 activation by its cognate ligand, EphrinB2, did not stimulate PDGFRβ; instead, apoptosis was paradoxically induced. Finally, we showed that small-molecule inhibition of both PDGFRβ and EphB4 by dasatinib resulted in a significant decrease in tumor cell viability in vitro, as well as decreased tumor growth rate and significantly prolonged survival in vivo. To our knowledge, these results are the first to identify EphB4 and its cross-talk with PDGFRβ as unexpected vital determinants of tumor cell survival in aRMS, with EphB4 at the crux of a bivalent signaling node that is either mitogenic or proapoptotic.
Insights
Alveolar rhabdomyosarcoma (aRMS) is a childhood cancer. Researchers found that targeting ephrin receptor B4 (EphB4) and PDGFRβ may offer new therapeutic strategies for this aggressive malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Alveolar rhabdomyosarcoma (aRMS) is an aggressive pediatric cancer, often presenting as metastatic disease.
- Identifying novel therapeutic targets is crucial for improving outcomes in aRMS.
Purpose of the Study:
- To identify novel therapeutic targets for alveolar rhabdomyosarcoma (aRMS).
- To investigate the role of receptor tyrosine kinases in aRMS pathogenesis and survival.
Main Methods:
- An unbiased tyrosine kinome RNA interference screen was conducted in a conditional mouse model of aRMS.
- Expression analysis of ephrin receptor B4 (EphB4) in human aRMS samples.
- Investigated cross-talk between EphB4 and PDGFRβ signaling pathways.
- Assessed the efficacy of dasatinib, a small-molecule inhibitor, in vitro and in vivo.
Main Results:
- Ephrin receptor B4 (EphB4) was identified as a target widely expressed in human aRMS, correlating with poor clinical outcome.
- Discovered cross-talk between EphB4 and PDGFRβ, influencing Akt and Erk1/2 pathways.
- EphB4 activation by EphrinB2 induced apoptosis, while PDGFRβ activation promoted cell survival.
- Dasatinib inhibition of both PDGFRβ and EphB4 reduced tumor cell viability, growth, and prolonged survival in vivo.
Conclusions:
- EphB4 and its cross-talk with PDGFRβ are critical determinants of tumor cell survival in aRMS.
- EphB4 acts as a bivalent signaling node, mediating either mitogenic or proapoptotic signals.
- Targeting EphB4 and PDGFRβ with dasatinib represents a promising therapeutic strategy for aRMS.
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