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.

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer.

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The Epidermal Growth Factor Receptor (EGFR) is overexpressed or mutated in human carcinomas and glioblastomas, which are tumors of epithelial and glial origin, respectively. Some publications indicated that EGFR overexpression could occur in human osteosarcomas (OS). Using EGFR knockout mice (Egfr-/-), we have recently shown that EGFR plays a role in bone development and osteoblast function, raising the possibility that EGFR is also involved in OS formation. Here we show that Egfrf/f Runx2-Cre mice (EgfrΔOb), lacking the EGFR in osteo-chondroprogenitor cells, develop an increased zone of hypertrophic chondrocytes in long bones and decreased bone formation. When bred to c-fos transgenic mice (H2-c-fosLTR) that develop osteosarcomas with 100% penetrance, EgfrΔOb mice show reduced tumor incidence and burden. At the molecular level, tumors from EgfrΔOb mice exhibit decreased expression levels of c-Fos and Cyclin D1. In vitro experiments in primary bone tumor cells further show that EGFR inhibition leads to reduced proliferation and increased apoptosis. Importantly, Egfr and c-Fos also play an important role in human OS, as co-expression of both proteins in tumor sections correlated with significantly reduced survival in patients suffering from primary OS. Taken together our data suggest an essential role of EGFR signaling during both development and progression of c-Fos-dependent OS and newly identified molecular targets currently under investigation will be presented. Citation Format: Markus Linder, Elisabeth Glitzner, Sriram Srivatsa, Parastoo Shahrouzi, Latifa Bakiri, Monika Dumanic, Markus Mitterhauser, Erwin F. Wagner, Maria Sibilia. The role of EGFR in c-fos-dependent osteosarcoma formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 530. doi:10.1158/1538-7445.AM2017-530