Type 1 Insulin-Like Growth Factor Receptor (IGF1R) Nuclear Localization in High-grade Glioma cells enhances Motility, Metabolism and in vivo Tumorigenesis

MARTIN AYELEN; FERNANDEZ, MARÍA CELIA; CATTANEO ELIZABETH; CLAUDIO DAVID SCHUSTER; VENARA MARCELA; CLEMENT, FLORENCIA; BERENSTEIN ARIEL; GARCIA LOMBARDI, M; IGNACIO BERGADÁ; MARIANA GUTIERREZ; MARCELO A MARTI; GONZALEZ BARO, MARIA; PENNISI PATRICIA A

Frontiers in Endocrinology

Frontiers Media

Lugar: Laussane; Año: 2022

Abstract: Gliomas are the most frequent solid tumors in children. Among these, high-grade gliomas are less common in childrenthan in adults, though are similar in their aggressive clinical behavior. The insulin-like growth factor 1 receptor (IGF1R) plays animportant role in cancer biology, and its nuclear localization has been described as an adverse prognostic factor in differenttumors.We have previously demonstrated that in pediatric gliomas, IGF1R nuclear localization is significantly associated with high-gradetumors, worst clinical outcome and increased risk of death. The present study was designed to explore the role of IGF1Rintracellular localization in the biology of glioblastoma (grade IV glioma) by in vitro and, using subcutaneous xenografts as a proofof concept, by in vivo studies. We used U87 cell line to develop a model in which IGF1R was able (U87WT 5) or unable (U87Mut 5 cells)to translocate to the nucleus. We found that IGF1R nuclear localization promotes cell motility without affecting cell proliferation ofcultured glioma cells. We present evidence that the increase in the metabolic activity depicted as a higher expression of glucosetransporters and stimulation in lipid biosynthesis and usage - in detriment of its accumulation -, is also favored in glioma cellswhen IGF1R is able to translocate to the nucleus. In vivo, IGF1R capacity to translocate to the nucleus allows not only a higherproliferation rate and earlier development of tumors, but also renders the cells sensitive to OSI906 therapy. With this work weprovide evidence that support the implications of the presence of IGF1R in the nucleus of glioma cells and introduce a potentialtherapeutic opportunity for patients harboring gliomas with IGF1R nuclear localization.