Endoglin, a novel biomarker and therapeutic target in malignant peripheral nerve sheath tumors
Title (trans.)
Endoglina, un nuevo biomarcador y diana terapéutica en tumores malignos de la vaina del nervio periféricoAuthor
González Muñoz, Maria TeresaAdvisor
Peinado Selgas, HéctorEntity
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Oncológicas (CNIO)Date
2022-04-29Subjects
Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 29-04-2022Esta tesis tiene embargado el acceso al texto completo hasta el 29-10-2023
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
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
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