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Theranostics 2020; 10(11):5120-5136. doi:10.7150/thno.41450 This issue Cite

Research Paper

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

Israel López-Valero^1,2,3*, David Dávila^1,2*, José González-Martínez^1,2, Nélida Salvador-Tormo^1,2, Mar Lorente^1,2,3, Cristina Saiz-Ladera^1,2,3, Sofía Torres¹, Estibaliz Gabicagogeascoa^1,2, Sonia Hernández-Tiedra^1,2, Elena García-Taboada^1,4, Marina Mendiburu-Eliçabe^1,2, Fátima Rodríguez-Fornés^5,6,7, Rebeca Sánchez-Domínguez^5,6,7, José Carlos Segovia^5,6,7, Pilar Sánchez-Gómez⁸, Ander Matheu^9,10,11, Juan M. Sepúlveda¹², Guillermo Velasco^1,2,3✉

1. Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, Madrid, Spain
2. Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
3. Instituto Universitario de Investigación Neuroquímica, Complutense University, 28040 Madrid, Spain
4. Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas.
5. Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
6. Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
7. Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
8. Neuro-oncology Unit, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
9. Cellular Oncology group, Biodonostia Health Research Institute, Spain
10. CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), Madrid, Spain
11. IKERBASQUE, Basque Foundation, Bilbao, Spain.
12. Neuro-oncology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain
*Equal contribution

✉ Corresponding author: Guillermo Velasco, Department of Biochemistry and Molecular Biology, School of Biology. Complutense University Calle José Antonio Nováis 12, 28040-Madrid, Spain. Phone: +34 913945034; E-mail: gvelascoes

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.

Keywords: glioblastoma, Midkine, ALK receptor tyrosine kinase, autophagy, SOX, combinational therapies

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