利用患者来源异种移植模型对转移性小细胞肺癌的蛋白质组学见解

Small cell lung cancer (SCLC) is one of the most aggressive solid malignancies with limited treatment options. Access to clinically relevant SCLC tissue is restricted because surgical resection is rare in metastatic disease, making this cancer type difficult to study. Through our multicenter rapid research autopsy (RRA) program, however, we are able to collect not only primary tumors but also multiple metastatic lesions, providing a unique and rare collection of SCLC specimens. In this program, rapid autopsies are performed within four hours after death to ensure optimal tissue quality for downstream analyses. In the current project, we analyzed samples from seven patients with histologically confirmed SCLC, including clinical and metastatic lesions, as well as their corresponding patient-derived tumor xenografts (PDTXs) serially passaged through three generations. To assess whether the original tissue architecture and intratumoral heterogeneity are preserved across PDTX generations, we performed immunohistochemical and proteomic analyses, comparing molecular profiles between the original tumors and their corresponding PDTX models. A subset of SCLC clinical specimens, including matched PDTX-clinical pairs, confirmed that the histologic landscape of the tumors of origin is preserved in the derivative PDTX models. Samples were grouped by patient and anatomical site, and pairwise Pearson correlations of global protein abundance profiles were computed within each group. The mean within-lineage correlation was high (typically >0.8), and correlation heatmaps showed tight clustering across PDTX generations from the same lineage. Across all patients, the only pathways consistently and significantly downregulated in PDTX models compared with the original tumors were the ECM-receptor interaction and Complement and Coagulation Cascade pathways. When analyzing metastatic PDTX samples, we compared liver and lymph node metastases with their corresponding primary patient tumors across PDTX generations. In lymph node metastases, proteins involved in ECM-receptor interaction and EMT pathways were upregulated. In contrast, liver metastases showed upregulation of fatty acid metabolism and peroxisome proliferator-activated receptor signaling pathways, with downregulation of EMT, ECM-receptor interaction, E2F targets, and G2M checkpoint. These findings demonstrate that the proteomic identity of SCLC tumors is largely preserved during serial passaging in PDTX models, while site-specific adaptations emerge in distinct metastatic microenvironments.