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Published on: April 4, 2025
Targeting EphA3 inhibits cancer growth by disrupting the tumor stromal microenvironment
Mary E Vail1, Carmel Murone2, April Tan3
1Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia. mary.vail@monash.edu Andrew.Scott@ludwig.edu.au Martin.Lackmann@monash.edu.
Abstract:
Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3(+)/CD90(+)/Sca1(+) mesenchymal/stromal cells with an EphA3 agonist leads to cell contraction, cell-cell segregation, and apoptosis. Treatment of mice with an agonistic α-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy.
Insights
EphA3, a receptor tyrosine kinase, is unexpectedly overexpressed in human cancers. Its activation inhibits tumor growth by disrupting the tumor microenvironment, suggesting EphA3 agonists as a novel anticancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Eph receptor tyrosine kinases (RTKs) are crucial for cell communication in tissue development and cancer.
- While some cancer genomes suggest EphA3 acts as a tumor suppressor, its role in oncogenesis is unclear.
- The expression patterns of EphA3 in tumors are not well understood.
Purpose of the Study:
- To investigate the expression pattern and function of EphA3 in the tumor microenvironment.
- To determine the therapeutic potential of targeting EphA3 in cancer.
Main Methods:
- Analysis of EphA3 expression in human cancers and mouse tumor xenografts.
- In vitro studies on EphA3 activation in mesenchymal/stromal cells.
- In vivo studies using agonistic α-EphA3 antibodies in mice.
Main Results:
- EphA3 is unexpectedly overexpressed in the tumor microenvironment of various cancers.
- Activation of EphA3 on mesenchymal/stromal cells induces cell contraction, segregation, and apoptosis.
- Treatment with an EphA3 agonist disrupts tumor stroma and microvasculature integrity, inhibiting tumor growth.
Conclusions:
- EphA3 is a novel target for selectively eliminating the tumor microenvironment.
- EphA3 agonists show potential as an anticancer therapeutic strategy.
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