Differential gene expression in SMC Ctrl vs TAZ4SA. Differential gene expression in SMC Ctrl vs TAZ4SA

Poor prognosis of small cell lung cancer (SCLC) is mainly attributed to its highly metastatic capability. Here we identify the SMC and Non-SMC from Rb1L/L/Trp53 L/L mouse model through FACS with NE and mensenchymal markers. In order to identify functions of these two subpopulations during SCLC malignant progression, we compared their metastatic capability by allograft experiment. In addition, we find that the SMC is progressively transited from the Non-SCLC during mouse SCLC malignant progression. Further investigation reveals that genetic disruption of the SWI/SNF chromatin-remodeling complex, in RP model abrogates SMC phenotype maintenance and SCLC metastasis. In search of important downstream regulators, we find that TAZ, the core transcription cofactor of the Hippo pathway, is epigenetically silenced by SWI/SNF complex during this process. Collectively, our data link phenotypic transition to cancer metastasis and identify TAZ as a critical molecular switch that controls SCLC plasticity. Overall design: SMC were derived from Rb1L/L, Trp53L/L mouse model through FACS. SMC was infected with the Ctrl or TAZ4SA (activated muation) virus. RNA-seq was performed to compare the gene expression profile between SMC with or without TAZ4SA overexpression. Three replicates for each sample were included.

小细胞肺癌（small cell lung cancer, SCLC）预后不佳主要源于其高转移潜能。本研究通过结合神经内分泌（neuroendocrine, NE）与间质标志物的流式细胞术（FACS），从Rb1L/L/Trp53L/L小鼠模型中分离得到SMC与非SMC亚群。为明确这两个亚群在SCLC恶性进展中的功能，我们通过同种异体移植实验对比了二者的转移能力。此外，我们发现在小鼠SCLC恶性进展过程中，SMC由非SMC亚群逐步转化而来。进一步研究揭示，在RP模型中，SWI/SNF染色质重塑复合物的遗传扰动会破坏SMC表型的维持与SCLC的转移能力。为探寻关键下游调控因子，我们发现Hippo通路的核心转录辅因子TAZ在此过程中被SWI/SNF复合物表观遗传沉默。综上，本研究将表型转化与癌症转移建立关联，并确定TAZ是调控SCLC可塑性的关键分子开关。实验整体设计：本研究从Rb1L/L、Trp53L/L小鼠模型中通过FACS分离得到SMC，将其分别感染对照（Ctrl）或TAZ4SA（激活突变型）病毒，随后通过RNA-seq比较过表达TAZ4SA与未过表达组的基因表达谱，每组样本设置3次生物学重复。