The transcriptomic and proteomic landscape of feline fibrosarcoma and matched normal tissue
Fibrosarcomas (FSA) are rare malignant soft tissue tumors characterized by low chemo- and radiosensitivity. The development of novel treatment strategies for human FSA is hindered by the low incidence of the disease and the absence of suitable clinical models. Interestingly, aggressive FSA occur more frequently in domestic cats, representing a clinically amenable model for assessing novel therapies such as targeted imaging or theranostics. However, a lack of molecular characterization of FSA and adjacent normal tissue (NT) in both species hinders identification of tumor-specific targets and undermines the translational potential of feline FSA. Combining laser-capture microdissection, RNA sequencing and LC-MS/MS, we perform comprehensive profiling of 30 feline FSA and matched skeletal muscle, adipose and connective tissue. Clear inter-tissue differences allow the identification of significantly upregulated and tumor-exclusive features that represent potential targets for diagnostic and therapeutic approaches. While feline FSA are characterized by hyperactive EIF2, TP53 and MYC signaling, immune-related and neuronal pathways emerge as modulators of tumor aggressiveness and immunosuppression. A high degree of molecular similarity with canine and human FSA allows the identification of conserved cross-species tumor targets. Significant enrichment in DNA repair pathways in feline FSA are shown to be associated with aggressive clinical behavior in human STS. Finally, we leverage the molecular profiles to identify vulnerabilities, including sensitivity to ATR and PARP inhibition as potential treatment for feline FSA. In conclusion, this detailed landscape provides a rich resource to identify target candidates and therapeutic vulnerabilities within and across species and supports feline FSA as relevant models for the human disease. Overall design: RNA sequencing was performed on 30 feline FSA and matched skeletal muscle, adipose and connective tissue.