Lineage-specific intolerance to oncogenic drivers restricts histological transformation [scRNA-Seq]

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC following treatment with targeted therapies. Here we designed models to follow the conversion of LUAD to SCLC and found the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells, transcriptionally resembling the pulmonary basal lineage. These findings suggest histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs. Single cell RNA sequencing was performed for 27 samples from genetically engineered mouse models. All samples were sorted from fresh, enzymatically dissociated lung tissues and, in most cases, triplicates were pooled before sequencing.

肺腺癌（Lung adenocarcinoma, LUAD）与小细胞肺癌（Small cell lung cancer, SCLC）被认为起源于肺部不同的上皮细胞类型。值得注意的是，接受靶向治疗后，肺腺癌可发生组织学转化为小细胞肺癌。本研究构建了追踪肺腺癌向小细胞肺癌转化的模型，发现组织学转化的核心障碍集中于对MYC（Myc）的耐受——我们证实MYC是肺神经内分泌细胞的谱系特异性驱动因子。组织学转化常伴随Akt信号通路的激活。调控该通路可使细胞获得对作为致癌驱动因子的MYC的耐受，从而产生罕见的干细胞样细胞，其转录特征与肺基底细胞谱系高度相似。上述发现提示，组织学转化可能需要基底干细胞固有的细胞可塑性，以耐受此前不相容的致癌驱动程序。本研究对基因工程小鼠模型的27份样本开展了单细胞RNA测序（Single cell RNA sequencing）。所有样本均从新鲜的经酶解解离的肺组织中分选获得，多数情况下会将三份生物学重复样本混合后再进行测序。