Lineage-specific intolerance to oncogenic drivers restricts histological transformation [ATAC-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. Bulk ATAC-sequencing was performed for 15 high quality libraries across 8 biological conditions.

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群。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。本研究构建了用于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屏障集中于对Myc（Myc）的耐受性——我们证实Myc是肺神经内分泌细胞的谱系特异性致癌驱动因子。组织学转化通常伴随Akt信号通路（Akt pathway）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的耐受性，进而产生罕见的干细胞样细胞群，其转录组特征类似于肺部基底细胞谱系。上述研究结果表明，组织学转化可能依赖于基底干细胞固有的细胞可塑性，从而使细胞能够耐受原本不相容的致癌驱动程序。本研究针对8种生物学条件下的15个优质文库开展了批量转座酶可及性染色质测序（Bulk ATAC-sequencing）。