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oai:docta.ucm.es:20.500.14352/63082025-08-28T12:51:44Zcom_20.500.14352_14col_20.500.14352_15

López Valero, Israel Dávila, David González Martínez, José Salvador-Tormo, Nélida Lorente Pérez, María Del Mar Saiz Ladera, Cristina Torres Pabón, Norma Sofía Gabicagogeascoa Corta, Estíbaliz Hernández-Tiedra, Sonia García Taboada, Elena Mendiburu-Eliçabe Garganta, Marina Rodríguez Fornés, Fátima Sánchez Domínguez, Rebeca Segovia Martínez, Juan Carlos Sánchez Gómez, Pilar Matheu Fernández, Ander Sepúlveda Salas, Juan Miguel Velasco Díez, Guillermo 2023-06-16T15:18:50Z 2023-06-16T15:18:50Z 2020 López-Valero I, Dávila D, González-Martínez J, Salvador-Tormo N, Lorente M, Saiz-Ladera C, et al. Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells. Theranostics 2020;10:5120–36. https://doi.org/10.7150/thno.41450. 10.7150/thno.41450 https://hdl.handle.net/20.500.14352/6308 1838-7640 https://doi.org/10.7150/thno.41450 Glioblastoma (GBM) is one of the most aggressive forms of cancer. It has been proposed that the presence within these tumors of a population of cells with stem-like features termed Glioma Initiating Cells (GICs) is responsible for the relapses that take place in the patients with this disease. Targeting this cell population is therefore an issue of great therapeutic interest in neuro-oncology. We had previously found that the neurotrophic factor MIDKINE (MDK) promotes resistance to glioma cell death. The main objective of this work is therefore investigating the role of MDK in the regulation of GICs. Methods: Assays of gene and protein expression, self-renewal capacity, autophagy and apoptosis in cultures of GICs derived from GBM samples subjected to different treatments. Analysis of the growth of GICs-derived xenografts generated in mice upon blockade of the MDK and its receptor the ALK receptor tyrosine kinase (ALK) upon exposure to different treatments. Results: Genetic or pharmacological inhibition of MDK or ALK decreases the self-renewal and tumorigenic capacity of GICs via the autophagic degradation of the transcription factor SOX9. Blockade of the MDK/ALK axis in combination with temozolomide depletes the population of GICs in vitro and has a potent anticancer activity in xenografts derived from GICs. Conclusions: The MDK/ALK axis regulates the self-renewal capacity of GICs by controlling the autophagic degradation of the transcription factor SOX9. Inhibition of the MDK/ALK axis may be a therapeutic strategy to target GICs in GBM patients. eng https://creativecommons.org/licenses/by/4.0/ open access ATTRIBUTION 4.0 INTERNATIONAL Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells journal article