RT Journal Article
T1 Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells
A1 López-Valero, Israel
A1 Dávila, David
A1 González-Martínez, José
A1 Salvador-Tormo, Nélida
A1 Lorente Pérez, Mar
A1 Saiz-Ladera, Cristina
A1 Torres, Sofía
A1 Gabicagogeascoa, Estíbaliz
A1 Hernández-Tiedra, Sonia
A1 García-Taboada, Elena
A1 Mendiburu-Eliçabe, Marina
A1 Rodríguez-Fornés, Fátima
A1 Sánchez-Domínguez, Rebeca
A1 Segovia, Juan Carlos
A1 Sánchez-Gómez, Pilar
A1 Matheu, Ander
A1 Sepúlveda, Juan M.
A1 Velasco, Guillermo
AB 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.
PB Ivyspring International Publisher
SN ESSN: 1838-7640
YR 2020
FD 2020-04-06
LK https://hdl.handle.net/20.500.14352/6308
UL https://hdl.handle.net/20.500.14352/6308
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020
NO Instituto de Salud Carlos III (ISCIII)/Fondo Europeo de Desarrollo Regional (FEDER
NO Fundación Mutua Madrileña
NO Fundació La Marató de TV3
NO Asociación Española contra el Cancer (AECC)
NO Voices Against Brain Cancer (US)
NO The Medical Cannabis Bike Tour Foundation(The Netherlands)
DS Docta Complutense
RD 1 may 2024