Maulding Nathan D, Zou Jun, Zhou Wei, Metcalfe Ciara, Stuart Joshua M, Ye Xin, Hafner Marc
gRED Computational Sciences, Genentech Inc, South San Francisco, CA, USA.
Department of Biomolecular Engineering and Bioinformatics, UC Santa Cruz, Santa Cruz, CA, USA.
NPJ Syst Biol Appl. 2025 Jan 10;11(1):5. doi: 10.1038/s41540-024-00485-8.
Understanding transcriptional heterogeneity in cancer cells and its implication for treatment response is critical to identify how resistance occurs and may be targeted. Such heterogeneity can be captured by in vitro studies through clonal barcoding methods. We present TraCSED (Transformer-based modeling of Clonal Selection and Expression Dynamics), a dynamic deep learning approach for modeling clonal selection. Using single-cell gene expression and the fitness of barcoded clones, TraCSED identifies interpretable gene programs and the time points at which they are associated with clonal selection. When applied to cells treated with either giredestrant, a selective estrogen receptor (ER) antagonist and degrader, or palbociclib, a CDK4/6 inhibitor, pathways dynamically associated with resistance are revealed. For example, ER activity is associated with positive selection around day four under palbociclib treatment and this adaptive response can be suppressed by combining the drugs. Yet, in the combination treatment, one clone still emerged. Clustering based on partial least squares regression found that high baseline expression of both SNHG25 and SNCG genes was the primary marker of positive selection to co-treatment and thus potentially associated with innate resistance - an aspect that traditional differential analysis methods missed. In conclusion, TraCSED enables associating features with phenotypes in a time-dependent manner from scRNA-seq data.
了解癌细胞中的转录异质性及其对治疗反应的影响对于确定耐药性如何产生以及如何靶向治疗至关重要。这种异质性可以通过体外研究中的克隆条形码方法来捕获。我们提出了TraCSED（基于Transformer的克隆选择和表达动态建模），一种用于克隆选择建模的动态深度学习方法。利用单细胞基因表达和条形码克隆的适应性，TraCSED识别出可解释的基因程序以及它们与克隆选择相关的时间点。当应用于用选择性雌激素受体（ER）拮抗剂和降解剂吉瑞司群或CDK4/6抑制剂哌柏西利处理的细胞时，揭示了与耐药性动态相关的途径。例如，在哌柏西利治疗下，ER活性在第四天左右与阳性选择相关，并且这种适应性反应可以通过联合用药来抑制。然而，在联合治疗中，仍有一个克隆出现。基于偏最小二乘回归的聚类发现，SNHG25和SNCG基因的高基线表达是对联合治疗阳性选择的主要标志物，因此可能与固有耐药性相关——这是传统差异分析方法所忽略的一个方面。总之，TraCSED能够从scRNA-seq数据中以时间依赖的方式将特征与表型联系起来。
