C3G Downregulation Induces The Acquisition Of A Mesenchymal ...
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Abstract
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.
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Conflict of interest statement
The authors declare no competing interests.
Figures

Fig. 1. C3G is downregulated in GBM…
Fig. 1. C3G is downregulated in GBM promoting changes in cell morphology.
A C3G (…
Fig. 2. C3G downregulation enhances invasion of…
Fig. 2. C3G downregulation enhances invasion of GBM cells promoting the expression of mesenchymal markers.

Fig. 3. Effect of C3G silencing on…
Fig. 3. Effect of C3G silencing on tumorigenic and proliferative properties of GBM cells.
Non-silenced…

Fig. 4. Effect of C3G knock-down on…
Fig. 4. Effect of C3G knock-down on in vivo tumor growth.
A Xenograft assay using…
Fig. 5. Effect of C3G knock-down on…
Fig. 5. Effect of C3G knock-down on EGFR activity and membrane localization.
U87 and U87shC3G…

Fig. 6. C3G downregulation increases the phosphorylation…
Fig. 6. C3G downregulation increases the phosphorylation of FGFR1 and other RTKs, promoting cell invasion.

Fig. 7. C3G downregulation enhances ERKs activation…
Fig. 7. C3G downregulation enhances ERKs activation in response to serum and FGF2, promoting invasion.

Fig. 8. Graphical abstract showing the function…
Fig. 8. Graphical abstract showing the function of C3G in glioblastoma.
C3G levels are high…
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