RT Journal Article
T1 C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells.
A1 Herranz, Óscar
A1 Rodrigo-Faus, María
A1 Jauregui, Patricia
A1 Morgner, Stephanie
A1 Rubio, Ignacio
A1 Guerrero, Carmen
A1 Porras, Almudena
A1 Gutiérrez Uzquiza, Álvaro
A1 Manzano Figueroa, Sara
A1 Bragado Domingo, Paloma
A1 Sequera Hurtado, Celia
AB Glioblastoma (GBM) is the most aggressive tumor from the central nervous system (CNS). The current lack of efficient therapies makes essential to find new treatment strategies. C3G, a guanine nucleotide exchange factor for some Ras proteins, plays a dual role in cancer, but its function in GBM remains unknown. Database analyses revealed a reduced C3G mRNA expression in GBM patient samples. C3G protein levels were also decreased in a panel of human GBM cell lines as compared to astrocytes. Based on this, we characterized C3G function in GBM using in vitro and in vivo human GBM models. We report here that C3G downregulation promoted the acquisition of a more mesenchymal phenotype that enhanced the migratory and invasive capacity of GBM cells. This facilitates foci formation in anchorage-dependent and -independent growth assays and the generation of larger tumors in xenografts and chick chorioallantoic membrane (CAM) assays, but with a lower cell density, as proliferation was reduced. Mechanistically, C3G knock-down impairs EGFR signaling by reducing cell surface EGFR through recycling inhibition, while upregulating the activation of several other receptor tyrosine kinases (RTKs) that might promote invasion. In particular, FGF2, likely acting through FGFR1, promoted invasion of C3G-silenced GBM cells. Moreover, ERKs mediate this invasiveness, both in response to FGF2- and serum-induced chemoattraction. In conclusion, our data show the distinct dependency of GBM tumors on C3G for EGF/EGFR signaling versus other RTKs, suggesting that assessing C3G levels may discriminate GBM patient responders to different RTK inhibition protocols. Hence, patients with a low C3G expression might not respond to EGFR inhibitors.
PB Springer Nature
YR 2021
FD 2021-01-01
LK https://hdl.handle.net/20.500.14352/133535
UL https://hdl.handle.net/20.500.14352/133535
LA eng
NO Manzano, S., Gutierrez-Uzquiza, A., Bragado, P. et al. C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells. Cell Death Dis 12, 348 (2021). https://doi.org/10.1038/s41419-021-03631-w
NO Ministerio de Economía y Competitividad (España)
NO Junta de Castilla y León (España)
NO European Commission
DS Docta Complutense
RD 18 mar 2026