Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, Italy.
Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
J Exp Clin Cancer Res. 2023 Jan 6;42(1):8. doi: 10.1186/s13046-022-02591-z.
Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics.
We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively.
PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs.
Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.
源自晚期结直肠癌（CRC）患者的患者来源类器官（PDO）可能是预测药物反应和发现新生物标志物的关键平台。我们旨在将 PDO 药物反应与基因组学以外的多组学特征相结合。
我们从 22 名晚期 CRC 患者中生成了 29 条 PDO 系，并进行了形态学、基因组和转录组特征分析。我们在五个长期培养物中用标准和非标准药物组合进行了药物敏感性测定，并分别通过 SWATH-MS 和 RNA-seq 分析将药物反应与基线蛋白质组学和转录组学特征相结合。
成功从经过大量预处理的患者中生成了 PDO，包括源自化疗前和化疗后肝转移的高级 MSI 高 CRC 的配对模型。我们的 PDO 忠实地再现了原始组织的基因组和表型特征。药物组测试确定了 PDO 之间的差异反应，特别是对奥沙利铂和帕博西尼的反应。蛋白质转录组分析表明，奥沙利铂无反应的 PDO 中 t-RNA 氨酰化过程富集，并表现出向氧化磷酸化途径依赖性的转变，而在一个 PDO 中检测到对帕博西尼的异常反应，该 PDO 中 MYC 激活和伴侣蛋白热休克蛋白 90 家族细胞溶质亚基 1A（HSP90AA1）和热休克蛋白 70kDa 家族成员 1A（HSPA1A）的富集，涉及蛋白质组完整性。蛋白质转录组数据融合在涉及药物差异反应的高度整合功能过程网络中证实了这些结果。
我们将 PDO 药物敏感性与 SWATH 质谱和 RNA-seq 相结合的策略使我们能够识别不同的基线蛋白和基因表达谱，这些谱具有预测治疗反应/耐药性的潜力，并有助于开发有效和个性化的癌症治疗方法。
