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.

纤维肉瘤（fibrosarcomas, FSA）是一类罕见的恶性软组织肿瘤，以对化疗与放疗敏感性低下为典型特征。由于该疾病发病率较低且缺乏合适的临床模型，人类纤维肉瘤的新型治疗策略开发进程受到阻碍。值得注意的是，家猫中侵袭性纤维肉瘤的发病更为频繁，其可作为评估靶向成像、治疗诊断学等新型疗法的临床适用模型。然而，这两个物种中纤维肉瘤及其邻近正常组织（normal tissue, NT）的分子特征研究存在缺失，这阻碍了肿瘤特异性靶点的识别，同时削弱了家猫纤维肉瘤的转化应用潜力。本研究结合激光捕获显微切割（laser-capture microdissection）、RNA测序（RNA sequencing）及液相色谱-串联质谱（LC-MS/MS）技术，对30例家猫纤维肉瘤样本及其配对的骨骼肌、脂肪和结缔组织开展了全面的分子特征分析。清晰的组织间差异使得研究人员能够识别出显著上调的肿瘤特异性特征，这些特征可作为诊断与治疗策略的潜在靶点。家猫纤维肉瘤以EIF2、TP53及MYC信号通路过度激活为特征，而免疫相关及神经元通路则成为肿瘤侵袭性与免疫抑制的调控因子。家猫纤维肉瘤与犬类及人类纤维肉瘤具有高度的分子相似性，这使得跨物种保守肿瘤靶点的识别成为可能。研究显示，家猫纤维肉瘤中DNA修复通路的显著富集，与人类软组织肉瘤（soft tissue sarcomas, STS）的侵袭性临床表型相关。最后，本研究借助分子特征谱识别出了治疗靶点脆弱性，其中包括对ATR（Ataxia Telangiectasia and Rad3-related kinase）及PARP（Poly(ADP-ribose) polymerase）抑制剂的敏感性，这可作为家猫纤维肉瘤的潜在治疗方案。综上，本研究构建的详细分子图谱为跨物种及物种内的候选靶点与治疗脆弱性的识别提供了宝贵资源，并证实家猫纤维肉瘤可作为人类相关疾病的相关研究模型。实验整体设计：对30例家猫纤维肉瘤样本及其配对的骨骼肌、脂肪和结缔组织开展RNA测序。