Ligand-dependent activation of EGFR in follicular dendritic cells sarcoma is sustained by local production of cognate ligands

PURPOSE: The aim of this study was to investigate the biological and clinical
significance of epidermal growth factor receptor (EGFR) signaling pathway in
follicular dendritic cell sarcoma (FDC-S).
EXPERIMENTAL DESIGN: Expression of EGFR and cognate ligands as well as activation
of EGFR signaling components was assessed in clinical samples and in a primary
FDC-S short-term culture (referred as FDC-AM09). Biological effects of the EGFR
antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on FDC-S cells
were determined in vitro on FDC-AM09. Direct sequencing of KRAS, BRAF, and PI3KCA
was conducted on tumor DNA.
RESULTS: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On
FDC-AM09, we could show that engagement of surface EGFR by cognate ligands drives
the survival and proliferation of FDC-S cells, by signaling to the nucleus mainly
via MAPK and STAT pathways. Among EGFR ligands, heparin-binding EGF-like growth
factor, TGF-α and Betacellulin (BTC) are produced in the tumor microenvironment
of FDC-S at RNA level. By extending this finding at protein level we found that
BTC is abundantly produced by FDC-S cells and surrounding stromal cells. Finally,
direct sequencing of tumor-derived genomic DNA showed that mutations in KRAS,
NRAS, BRAF, and PI3KCA, which predicts resistance to anti-EGFR MoAb in other
cancer models, are not observed in FDC-S.
CONCLUSION: Activation of EGFR by cognate ligands produced in the tumor
microenvironment sustain viability and proliferation of FDC-S indicating that the
receptor blockade might be clinically relevant in this neoplasm.