Here, we report that the integrin αvβ8 and its latent transforming growth factor β1 (TGFβ1) protein ligand have central roles in promoting niche co-option and GBM initiation.
Taken together, our data demonstrate that metformin inhibits TGF-β1-induced EMT-like process and cancer stem-like properties in GBM cells <i>via</i> AKT/mTOR/ZEB1 pathway and provide evidence of metformin for further clinical investigation targeted GBM.
Hepatic expression of IGFBPrP1, α-smooth muscle actin (α-SMA), transforming growth factor β 1 (TGFβ1), collagen I, MMPs/TIMPs, Sonic Hedgehog (Shh), and glioblastoma family transcription factors (Gli1) were investigated by immunohistochemical staining and Western blotting analysis.
More than 1700 proteins were quantified, and bioinformatics predicted activations of MYC, NFE2L2, FN1, and TGFβ1 and inhibition of TP53 in GBM-EV stimulated astrocytes that were then confirmed by qPCR.
Experiments with cell lines, patient serum and tissue identified IL1B, CSF3 and TIMP1 as potential plasma markers and VIM, STC1, TGFB1 and HMOX1 as potential biopsy markers for GBM.
These effects were further detected in other GBM cell lines tested and also in co-cultures of hADSCs and U-87 MG. hADSC CM did not compromise lysosomal acidification; however, it was able to activate mTORC1 signaling and, as a consequence, led to a decrease in the nuclear translocation of TFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy, thereby contributing to a defective autophagic process. hADSCs secrete transforming growth factor beta 1 (TGFβ1) and this cytokine is an important mediator of CM effects on autophagy.