Endoglin, a novel biomarker and therapeutic target in malignant peripheral nerve sheath tumors

Resumen

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that represent an important clinical challenge due to their high tendency to relapse and metastasize and their relatively poor response to conventional therapies. Likewise, targeted agents have thus far failed to demonstrate clinical efficacy in MPNSTs. Therefore, there is a significant lack of known effective treatments for these patients, which underscores the urgent need for new therapeutic strategies. In this PhD thesis, we attempted to identify mediators of MPNST pathogenesis, aiming to find novel therapeutic opportunities. Based on preliminary data from our laboratory, we focused on investigating the potential role of the TGF-β coreceptor endoglin (ENG) in MPNST malignancy and progression. We have discovered that ENG is upregulated in both tumor and endothelial cells of human MPNSTs and, its expression correlates with advanced stages of the disease (i.e. local recurrence and distant metastasis). Moreover, we observed increased ENG levels in plasma circulating small extracellular vesicles from patients with MPNSTs. Mechanistically, we revealed that ENG modulates the activation of the SMAD1/5 and MAPK/ERK signaling pathways and the expression of pro-metastatic and pro-angiogenic genes in the STS26T and ST88-14 human MPNST cell lines. Our data also demonstrate an active role for tumor cell-specific ENG in MPNST progression in vivo, positively regulating both tumor cell proliferation and tumor-associated angiogenesis in STS26T tumors. Therapeutically, we found that the anti-ENG antibodies TRC105 and M1043 impair tumor growth and lymph node metastasis in STS26T and ST88-14 xenograft models, reducing tumor cell proliferation, metastatic ability and angiogenesis. Notably, the combination of these anti-ENG therapies with the MEK inhibitor PD-901 synergistically inhibited tumor growth, and almost abolished spontaneous and experimental metastasis in STS26T xenograft models. The analysis of the mechanisms involved showed that ENG targeting cooperates with MEK inhibition to block the activation of the Smad1/5 and MAPK/ERK pathways in both STS26T and ST88-14 cells and to decrease tumor cell proliferation and angiogenesis in primary tumors. Overall, 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. Notably, we also provide preclinical evidence that dual pharmacological inhibition of ENG and MEK represents an attractive approach for the treatment of these tumors