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Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells

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López-Valero, Israel and Dávila, David and González-Martínez, José and Salvador-Tormo, Nélida and Lorente Pérez, Mar and Saiz-Ladera, Cristina and Torres, Sofía and Gabicagogeascoa, Estíbaliz and Hernández-Tiedra, Sonia and García-Taboada, Elena and Mendiburu-Eliçabe, Marina and Rodríguez-Fornés, Fátima and Sánchez-Domínguez, Rebeca and Segovia, Juan Carlos and Sánchez-Gómez, Pilar and Matheu, Ander and Sepúlveda, Juan M. and Velasco, Guillermo (2020) Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells. Theranostics, 10 (11). pp. 5120-5136. ISSN ESSN: 1838-7640

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Official URL: https://www.thno.org/v10p5120.htm



Abstract

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.


Item Type:Article
Uncontrolled Keywords:Glioblastoma; Midkine; ALK receptor tyrosine kinase; Autophagy; SOX; Combinational therapies
Subjects:Medical sciences > Medicine > Oncology
Medical sciences > Biology > Molecular biology
Medical sciences > Biology > Biochemistry
ID Code:60826
Deposited On:09 Jun 2020 10:43
Last Modified:10 Jun 2020 07:04

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