Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses
Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses
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网格单细胞筛选揭示了患者源性类器官药物反应的基质调节
DOI：
10.1101/2022.10.19.512668
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Zapatero M
中科院分区：
文献类型：
--
作者：
Zapatero M
患者源性类器官（PDO）可以模拟个性化治疗反应，但目前的筛选技术无法揭示药物反应机制或研究肿瘤微环境细胞如何改变治疗性能。为了解决这个问题，我们开发了一种高度多路复用的质谱流式细胞术平台，以单细胞分辨率测量> 2，500个结直肠癌（CRC）PDO和癌症相关成纤维细胞（CAF）中对临床治疗的反应的翻译后修饰（PTM）信号。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，我们开发了Trellis-一种高度可扩展的、基于层次树的治疗效果分析方法。网格单细胞筛选显示，靶细胞周期阻滞和DNA损伤药物作用是常见的，即使在化疗难治性PDO中也是如此。然而，药物诱导的细胞凋亡是患者特异性的。我们发现药物诱导的细胞凋亡与基因型或临床分期无关，但与PDO中细胞内在的PTM信号传导一致。CAF通过将癌细胞转变为慢循环细胞状态来保护化学敏感的PDO，并且CAF化学保护可以通过抑制雅普来逆转。亮点> 2，500个来自药物处理的PDO和CAF的单细胞PTM信号传导、DNA损伤、细胞周期和凋亡反应。网格：用于单细胞筛选分析的基于层次树的治疗效果方法。PDO具有与细胞-CAF通过经由雅普信号传导改变PDO细胞状态来化学保护PDO。
Patient-derived organoids (PDOs) can model personalized therapy responses, however current screening technologies cannot reveal drug response mechanisms or study 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 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 developedTrellis— a highly-scalable, hierarchical 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 patient-specific. We found drug-induced apoptosis does not correlate with genotype or clinical staging but does align with cell-intrinsic PTM signaling in PDOs. CAFs protect chemosensitive PDOs by shifting cancer cells into a slow-cycling cell-state and CAF chemoprotection can be reversed by inhibiting YAP.Highlights>2,500 single-cell PTM signaling, DNA-damage, cell-cycle, and apoptosis responses from drug-treated PDOs and CAFs.Trellis: hierarchical tree-based treatment effect method for single-cell screening analysis.PDOs have patient-specific drug responses that align with cell-intrinsic PTM signaling states.CAFs chemoprotect PDOs by altering PDO cell-state via YAP signaling.
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影响因子：
28.2
作者：
Pauli C;Hopkins BD;Prandi D;Shaw R;Fedrizzi T;Sboner A;Sailer V;Augello M;Puca L;Rosati R;McNary TJ;Churakova Y;Cheung C;Triscott J;Pisapia D;Rao R;Mosquera JM;Robinson B;Faltas BM;Emerling BE;Gadi VK;Bernard B;Elemento O;Beltran H;Demichelis F;Kemp CJ;Grandori C;Cantley LC;Rubin MA
通讯作者：
Rubin MA
影响因子：
28.2
作者：
Tiriac H;Belleau P;Engle DD;Plenker D;Deschênes A;Somerville TDD;Froeling FEM;Burkhart RA;Denroche RE;Jang GH;Miyabayashi K;Young CM;Patel H;Ma M;LaComb JF;Palmaira RLD;Javed AA;Huynh JC;Johnson M;Arora K;Robine N;Shah M;Sanghvi R;Goetz AB;Lowder CY;Martello L;Driehuis E;LeComte N;Askan G;Iacobuzio-Donahue CA;Clevers H;Wood LD;Hruban RH;Thompson E;Aguirre AJ;Wolpin BM;Sasson A;Kim J;Wu M;Bucobo JC;Allen P;Sejpal DV;Nealon W;Sullivan JD;Winter JM;Gimotty PA;Grem JL;DiMaio DJ;Buscaglia JM;Grandgenett PM;Brody JR;Hollingsworth MA;O'Kane GM;Notta F;Kim E;Crawford JM;Devoe C;Ocean A;Wolfgang CL;Yu KH;Li E;Vakoc CR;Hubert B;Fischer SE;Wilson JM;Moffitt R;Knox J;Krasnitz A;Gallinger S;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
46.9
作者：
Moon, Kevin R.;van Dijk, David;Krishnaswamy, Smita
通讯作者：
Krishnaswamy, Smita
影响因子：
78.5
作者：
Sahai, Erik;Astsaturov, Igor;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
50.3
作者：
Letai A;Bhola P;Welm AL
通讯作者：
Welm AL