Figueiredo Marxa L, Utturkar Sagar, Kumar Shreya, Fonseca-Alves Carlos Eduardo
Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
Purdue Institute for Cancer Research Computational Genomics, Purdue University, West Lafayette, IN, 47907, USA.
Cell Insight. 2024 Jul 14;3(5):100184. doi: 10.1016/j.cellin.2024.100184. eCollection 2024 Oct.
The present study focused on comparing the gene expression profiles of different mouse models of prostate cancer, focusing on the TRAMP transgenic model and its derived cell lines and extending the comparisons to relevant genetically engineered mouse models and human prostate cancer datasets. Employing RNA sequencing, we examined different levels of prostate cancer aggressiveness from the original TRAMP cells to the TRAMP-C2 (TC2) derived cell line and extending to the aggressive TC2-Ras (TC2R) cells and tumors. TC2R acquire the ability to grow in bone tissue upon implantation, unlike the parental TC2 cells. Analysis identified upregulated genes in cell cycle regulation, immune response, and mitotic processes in TRAMP compared to wild-type tissues. TC2 cells exhibited unique gene profiles enriched in ECM organization and tissue development pathways, while TC2R cells showed increased cytokine signaling and motility genes, with decreased ECM and immune response pathways. TC2R models demonstrated enhanced ECM organization and receptor tyrosine kinase signaling in tumors, notably enriching immune processes and collagen degradation pathways in intratibial tumors. Comparative analysis among mouse and human datasets showed overlaps, particularly in pathways relating to mitotic cycle regulation, ECM organization, and immune interactions. A gene signature identified in TC2R tumors correlated with aggressive tumor behavior and poor survival in human datasets. Further immune cell landscape analysis of TC2R tumors revealed altered T cell subsets and macrophages, confirmed in single-cell RNA-seq from human samples. TC2R models thus hold significant promise in helping advance preclinical therapeutics, potentially contributing to improved prostate cancer patient outcomes.
本研究聚焦于比较前列腺癌不同小鼠模型的基因表达谱，重点关注TRAMP转基因模型及其衍生的细胞系，并将比较扩展至相关的基因工程小鼠模型和人类前列腺癌数据集。通过RNA测序，我们研究了从原始TRAMP细胞到TRAMP-C2（TC2）衍生细胞系，再到侵袭性TC2-Ras（TC2R）细胞和肿瘤等不同程度的前列腺癌侵袭性。与亲代TC2细胞不同，TC2R植入后获得了在骨组织中生长的能力。分析发现，与野生型组织相比，TRAMP中细胞周期调控、免疫反应和有丝分裂过程中的基因上调。TC2细胞表现出独特的基因谱，富含细胞外基质（ECM）组织和组织发育途径，而TC2R细胞显示细胞因子信号传导和运动基因增加，ECM和免疫反应途径减少。TC2R模型显示肿瘤中ECM组织和受体酪氨酸激酶信号增强，特别是在胫骨内肿瘤中丰富了免疫过程和胶原蛋白降解途径。小鼠和人类数据集之间的比较分析显示存在重叠，特别是在与有丝分裂周期调控、ECM组织和免疫相互作用相关的途径中。在TC2R肿瘤中鉴定出的基因特征与人类数据集中的侵袭性肿瘤行为和不良生存相关。对TC2R肿瘤的进一步免疫细胞景观分析揭示了T细胞亚群和巨噬细胞的改变，这在人类样本的单细胞RNA测序中得到了证实。因此，TC2R模型在帮助推进临床前治疗方面具有巨大潜力，可能有助于改善前列腺癌患者的预后。
