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Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and
Teresa González-Muñoz1, Angela Di Giannatale2, Susana García-Silva1
1Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Purpose:
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFβ coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs.
Experimental Design:
ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis, were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models.
Results:
ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma-circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis.
Conclusions:
Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.
Insights
Endoglin (ENG) promotes malignant peripheral nerve sheath tumor (MPNST) growth and metastasis by enhancing angiogenesis and signaling pathways. Targeting ENG with antibodies, alone or with MEK inhibitors, shows therapeutic promise for MPNSTs.
Area of Science:
- Oncology
- Molecular Biology
- Angiogenesis Research
Background:
- Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited treatment options.
- Tumor angiogenesis is crucial for MPNST progression, necessitating identification of new therapeutic targets.
- Endoglin (ENG), a TGFβ coreceptor, plays a key role in angiogenesis.
Purpose of the Study:
- To investigate endoglin (ENG) as a potential therapeutic target in MPNSTs.
- To evaluate the role of ENG in MPNST pathogenesis, including its effects on angiogenesis and metastasis.
- To assess the efficacy of targeting ENG in preclinical MPNST models.
Main Methods:
- Assessed ENG expression in human MPNST tissues and plasma.
- Investigated the impact of ENG on gene expression and signaling pathways (Smad1/5, MAPK/ERK) in MPNST cells.
- Evaluated the in vivo effects of ENG on MPNST growth and metastasis in xenograft models.
- Tested the efficacy of anti-ENG antibodies (TRC105/M1043) as monotherapy and in combination with MEK inhibitors.
Main Results:
- ENG expression was upregulated in MPNST tissues and plasma-circulating extracellular vesicles.
- ENG modulates pro-angiogenic and pro-metastatic gene expression and activates Smad1/5 and MAPK/ERK pathways.
- Targeting ENG with neutralizing antibodies reduced MPNST growth, proliferation, and metastasis in vivo.
- Combination therapy with anti-ENG antibodies and MEK inhibitors demonstrated enhanced reduction in tumor growth and angiogenesis.
Conclusions:
- Endoglin (ENG) exhibits a tumor-promoting function in MPNSTs.
- ENG is a promising therapeutic target and potential biomarker for MPNSTs.
- Combined targeting of ENG and MEK pathways offers a potential therapeutic strategy for MPNST treatment.
