A PDGFRB-CD44-MIF crosstalk promotes cancer-associated cellular phenotypes in ATRT-TYR/MYC cell lines.

OBJECTIVE

Atypical teratoid/rhabdoid tumor (ATRT) is the most common brain tumor in children less than one-year-old. Previous studies have identified three epigenetic subgroups of ATRT: ATRT-SHH, ATRT-TYR, and ATRT-MYC. Interestingly, it was found that ATRT-TYR/MYC (mesenchymal) subgroups are sensitive to receptor-tyrosine kinase inhibitors (RTKIs), particularly those that inhibit the platelet-derived growth factor receptor B (PDGFRB), highlighting the importance of PDGF signaling in ATRTs. In addition, the ATRT-TYR/MYC subgroups show upregulation of the macrophage migration inhibitory factor (MIF), with dysregulation of the MIF signaling pathway, which was found to have immunosuppressive effects in other cancers. While PDGF and MIF pathways have been found to promote tumorigenesis of other cancers including glioma, their roles in ATRTs remain unknown. We hypothesized that PDGF and MIF signaling pathways contribute to maintaining malignant phenotypes in ATRT-TYR/MYC subgroups.

METHODS

To test this hypothesis, our project aimed to characterize PDGF signaling and investigate PDGF-MIF crosstalk in ATRT-TYR/MYC subgroups, using CRISPR/Cas9 stable knockouts (KOs) of various PDGF receptor and ligands.

RESULTS

We have shown that the PDGF pathway primarily promotes maintenance of malignant phenotypes in ATRT-TYR/MYC via modulation of the cell cycle. Furthermore, our studies reveal a plausible PDGFRB, MIF, and CD44 oncogenic signaling axis, that could modulate invasion and cellular phenotypic plasticity in ATRT-TYR/MYC, via regulation of neural stemness and epithelial-mesenchymal transition (EMT) marker expression.

CONCLUSIONS

Our collective study findings point to an important role for PDGFRB-MIF-CD44 signaling in the maintenance of malignant cellular phenotypes in ATRT-TYR/MYC cell lines.