Rhabdomyosarcoma study with RNA-Seq data on dbGaP (10 participants)

phs004009 — Involvement of the FGF8/FGF Receptor Signaling Pathway in the Maintenance    and Progression of Fusion-Positive Rhabdomyosarcoma

<p>In our previous work, we used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to demonstrate that <a href="https://www.ncbi.nlm.nih.gov/gene/2253">FGF8</a>, a target of the <a href="https://www.ncbi.nlm.nih.gov/gene/5077">PAX3</a>-<a href="https://www.ncbi.nlm.nih.gov/gene/2308">FOXO1</a> (P3F) transcription factor, is essential for tumorigenicity driven by P3F. When aberrantly expressed, FGF8 can also sustain tumorigenicity in recurrent tumors that are independent of P3F. In this study, we report that FGF8, along with its receptors <a href="https://www.ncbi.nlm.nih.gov/gene/2260">FGFR1</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/2264">FGFR4</a>, is often highly expressed in FP-RMS tumors. We found that high levels of FGF8 expression in FP-RMS cells correlate with increased sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Conversely, downregulating FGF8 led to a loss of sensitivity to these inhibitors. </p><p>Interestingly, when FGF8 was upregulated in myoblasts, it resulted in decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. The downregulation of FGFR4 expression mediated by FGF8 could be reversed by inhibiting FGFR1, <a href="https://www.ncbi.nlm.nih.gov/gene/5604">MEK</a>, or <a href="https://www.ncbi.nlm.nih.gov/gene/5594">ERK</a>, thereby defining a signaling pathway through which FGF8 exerts its regulatory effects. Additionally, we discovered that high FGF8 expression in P3F-independent recurrent tumors is due to a rearrangement of viral long terminal repeat (LTR) sequences into the 3' untranslated region (UTR) of FGF8, leading to increased stability of FGF8 mRNA. These findings indicate that FGF8 plays an oncogenic role in FP-RMS through FGFR4 and may also exert oncogenic effects in P3F-independent relapses via FGFR1. Our study highlights the functional significance of FGF8 in FP-RMS and supports the rationale for preclinical investigations of FGFR inhibitors in treating this type of cancer.</p>