Person:
Ramírez-González, María A

Profile Picture
First Name
María A
Last Name
Ramírez-González
Institution
ISCIII
Centrre
ISCIII::Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)
CNIC Organization
CNIO Organization
Institute
Identifiers
ORCID

Filters

2022 - 20232
Reset filters

Settings

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication
    On optimal temozolomide scheduling for slowly growing glioblastomas
    (Oxford University Press, 2022-09) Segura-Collar, Berta; Jiménez-Sánchez, Juan; Gargini, Ricardo; Dragoj, Miodrag; Sepúlveda-Sánchez, Juan M; Pešić, Milica; Ramírez-González, María A; Ayala-Hernández, Luis E; Sánchez-Gómez, Pilar; Pérez-García, Víctor M; James S. McDonnell Foundation; Ministry of Education, Science and Technological Development (Serbia); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; University of Castilla-La Mancha (España)
    Background: Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes. Methods: Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study. Results: Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients. Conclusions: In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs.
  • Thumbnail Image
    Publication
    Schnurri-3 drives tumor growth and invasion in cancer cells expressing interleukin-13 receptor alpha 2
    (Nature Publishing Group, 2023-11-14) Bartolomé, Rubén A; Martín-Regalado, Ángela; Pintado-Berninches, Laura; Robles, Javier; Ramírez-González, María A; Boukich, Issam; Sánchez-Gómez, Pilar; Balyasnikova, Irina V; Casal, J Ignacio; Ministerio de Universidades (España); Comunidad de Madrid (España); Unión Europea. Comisión Europea. NextGenerationEU; Agencia Estatal de Investigación (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos); Instituto de Salud Carlos III
    Interleukin 13 receptor alpha 2 (IL13Rα2) is a relevant therapeutic target in glioblastoma (GBM) and other tumors associated with tumor growth and invasion. In a previous study, we demonstrated that protein tyrosine phosphatase 1B (PTP1B) is a key mediator of the IL-13/IL13Rα2 signaling pathway. PTP1B regulates cancer cell invasion through Src activation. However, PTP1B/Src downstream signaling mechanisms that modulate the invasion process remain unclear. In the present research, we have characterized the PTP1B interactome and the PTP1B-associated phosphoproteome after IL-13 treatment, in different cellular contexts, using proteomic strategies. PTP1B was associated with proteins involved in signal transduction, vesicle transport, and with multiple proteins from the NF-κB signaling pathway, including Tenascin-C (TNC). PTP1B participated with NF-κB in TNC-mediated proliferation and invasion. Analysis of the phosphorylation patterns obtained after PTP1B activation with IL-13 showed increased phosphorylation of the transcription factor Schnurri-3 (SHN3), a reported competitor of NF-κB. SHN3 silencing caused a potent inhibition in cell invasion and proliferation, associated with a down-regulation of the Wnt/β-catenin pathway, an extensive decline of MMP9 expression and the subsequent inhibition of tumor growth and metastasis in mouse models. Regarding clinical value, high expression of SHN3 was associated with poor survival in GBM, showing a significant correlation with the classical and mesenchymal subtypes. In CRC, SHN3 expression showed a preferential association with the mesenchymal subtypes CMS4 and CRIS-B. Moreover, SHN3 expression strongly correlated with IL13Rα2 and MMP9-associated poor prognosis in different cancers. In conclusion, we have uncovered the participation of SNH3 in the IL-13/IL13Rα2/PTP1B pathway to promote tumor growth and invasion. These findings support a potential therapeutic value for SHN3.