EGFR is required for FOS‐dependent bone tumor development via RSK2/CREB signaling

Abstract

Osteosarcoma (OS) is a rare tumor of the bone occurring mainly in young adults accounting for 5% of all childhood cancers. Because of the limited therapeutic options, there has been no survival improvement for OS patients in the past 40 years. The epidermal growth factor receptor (EGFR) is highly expressed in OS; however, its clinical relevance is unclear. Here, we employed an autochthonous c‐Fos‐dependent OS mouse model (H2‐c‐fosLTR) and human OS tumor biopsies for preclinical studies aimed at identifying novel biomarkers and therapeutic benefits of anti‐EGFR therapies. We show that EGFR deletion/inhibition results in reduced tumor formation in H2‐c‐fosLTR mice by directly inhibiting the proliferation of cancer‐initiating osteoblastic cells by a mechanism involving RSK2/CREB‐dependent c‐Fos expression. Furthermore, OS patients with co‐expression of EGFR and c‐Fos exhibit reduced overall survival. Preclinical studies using human OS xenografts revealed that only tumors expressing both EGFR and c‐Fos responded to anti‐EGFR therapy demonstrating that c‐Fos can be considered as a novel biomarker predicting response to anti‐EGFR treatment in OS patients.

Wnt signaling and Loxl2 promote aggressive osteosarcoma

“…FOS and EGFR expression correlated in OS samples (Supplementary information, Fig. S10e ), as previously reported, 27 and LOXL2-immunoreactivity was over-represented in the EGFR/FOS double-positive samples compared to double-negative OS (Supplementary information, Fig. S10f ).…”

“…S4a ) and 143b OS cell lines. 27 Decreased mRNA expression of WNT7B and, to a lesser extent, WNT9A was observed when FOS was knocked down (Supplementary information, Fig. S4b, d ).…”

“…c-Jun/AP-1 was previously shown to modulate murine Wnt9a expression in the developing joint primordium through binding to a different Wnt9a promoter region. 67 On the other hand, c-Fos protein expression and stability is maintained through EGFR signaling and its downstream kinase RSK2 and both are required for c-Fos-dependent OS development 26 , 27 with c-Jun likely being the essential AP-1 dimerizing partner 68 (Fig. 8 ).…”

“…c-Fos-induced OS requires EGFR signaling and its downstream kinase RSK2. 26 , 27 Importantly, H2- c-fos LTR mice exhibit numerous hallmarks of the human disease, such as early-onset tumor development in long bones and heterogeneous histology. 25 , 28 , 29 …”

MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma by targeting epidermal growth factor receptor and proliferating cell nuclear antigen

“…However, the high expression of EGFR demonstrated better prognosis in OS (20). The EGFR protein was expressed highly in OS samples (21). Another previous study suggested that the interaction between transforming growth factor-α and EGFR elicited PI3K and AKT activation, which in turn activated nuclear factor-κB, resulting in the expression of intracellular adhesion molecule 1 and contributing to the migration of human OS cells (22).…”