英国伦敦大学学院癌症研究所Christopher J. Tape和美国耶鲁大学Smita Krishnaswamy共同合作，近期取得重要工作进展。他们基于网格树分析揭示患者来源类器官药物反应的基质调节机制。相关研究成果2023年12月7日在线发表于《细胞》杂志上。
据介绍，患者来源的类器官（PDO）可以对个性化的治疗反应进行建模；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，研究人员开发了一种高度复用的质谱细胞仪平台，以单细胞分辨率测量>2500例癌症（CRC）PDO和癌症相关成纤维细胞（CAF）的翻译后修饰（PTM）信号传导、DNA损伤、细胞周期活性和细胞凋亡，以响应临床治疗。为了在数千个单细胞数据集中比较患者和微环境特异性药物反应，研究人员开发了“网格”——一种高度可扩展的、基于树的治疗效果分析方法。Trellis单细胞筛选显示，靶向细胞周期阻断和DNA损伤药物效应很常见，即使在化学难治性PDO中也是如此。然而，药物诱导的细胞凋亡是罕见的，患者特异性的，并且与癌症细胞PTM信号一致。
总之，研究人员发现CAF可以调节PDO的可塑性，将增生性结肠干细胞（proCSC）转变为缓慢循环的结肠干细胞再生（revCSC），以保护癌症细胞免受化疗。
附：英文原文
Title: Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses
Author: María Ramos Zapatero, Alexander Tong, James W. Opzoomer, Rhianna O’Sullivan, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Callum Nattress, Xiao Qin, Jeroen Claus, Daniel Hochhauser, Smita Krishnaswamy, Christopher J. Tape
Issue&Volume: 2023/12/07
Abstract: 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.
DOI: 10.1016/j.cell.2023.11.005
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01220-5