Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses
Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses
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DOI：
10.1016/j.cell.2023.11.005
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发表时间：
2023-12-07
期刊：
影响因子：
64.5
通讯作者：
Tape，Christopher J.
中科院分区：
文献类型：
--
作者：
Zapatero，Maria Ramos;Tong，Alexander;Tape，Christopher J.
患者衍生的有机化合物(PDO)可以模拟个性化的治疗反应；然而，目前的筛选技术无法揭示药物反应机制或肿瘤微环境细胞如何改变治疗性能。为了解决这一问题，我们开发了一个高度多元化的质量细胞术平台，以单细胞分辨率测量翻译后修饰(PTM)信号、DNA损伤、细胞周期活动和细胞凋亡，以响应临床治疗的>；2,500结直肠癌(CRC)PDO和癌症相关成纤维细胞(CAF)。为了在数千个单细胞数据集中比较患者和微环境特定的药物反应，我们开发了“Trellis”-一种高度可扩展的、基于树的治疗效果分析方法。格子单细胞筛选显示，靶细胞周期阻断和DNA损伤药物效应很常见，即使在化疗耐药的PDO中也是如此。然而，药物诱导的细胞凋亡是罕见的，患者特有的，并与癌细胞PTM信号相一致。我们发现CAF可以调节PDO的可塑性，将增殖性结肠干细胞(ProCSCs)转变为慢周期复苏的结肠干细胞(RevCSCs)，以保护癌细胞免受化疗的影响。
Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post-translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed "Trellis"—a highly scalable, tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity—shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy.