Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [RNA-seq]. Acquired anoikis resistance mediates enhancer-driven subtype plasticity in pancreatic cancer [RNA-seq]

Genetic aberrations, including mutations or deletions in KRAS, TP53, SMAD4, and CDKN2A, are common causes of pancreatic ductal adenocarcinoma (PDA). Recent large-scale transcriptomic studies demonstrated that heterogeneous gene expressions played an essential role in determining molecular subtypes of PDA, although it remains unclear what the biological cues and consequences of distinct transcriptional programs are. Here, we describe an anoikis-induction-based experimental model that enforces the transition toward a squamous subtype of PDA cells. Characteristics of the squamous subtype, represented by aggressive behaviors, are faithfully recapitulated in vitro and in vivo, demonstrating the physiological relevance of this model. Integrated analysis of epigenome and transcriptome reveals that squamous subtype PDA cells acquire pro-angiogenic enhancer activity of which is sustained by the transcription factor TEAD2. Genetic and pharmacological inhibition of TEAD2 of these tumor cells impairs their pro-angiogenic phenotypes in vitro and cancer progression in vivo. Furthermore, we found that CD109 is a critical TEAD2 target that retains activated JAK-STAT signaling. Together, our findings implicate a TEAD2-CD109-JAK/STAT axis as a potential therapeutic vulnerability concealed in the squamous subtype-associated epigenome of pancreatic cancer cells. Overall design: RNA-seq profilings of various PDA cell lines

遗传畸变（包括KRAS、TP53、SMAD4及CDKN2A的突变或缺失）是胰腺导管腺癌（PDA）的常见致病因素。近期大规模转录组学研究表明，基因表达异质性在决定PDA分子亚型的过程中发挥关键作用，但目前仍不明确不同转录程序的生物学诱因与结局。本研究构建了一种基于失巢凋亡（anoikis）诱导的实验模型，可诱导PDA细胞向鳞状细胞亚型转化。以侵袭性行为为代表的鳞状细胞亚型特征，可在体外及体内被忠实重现，证实了该模型的生理学相关性。表观基因组与转录组联合分析显示，鳞状亚型PDA细胞获得了促血管生成增强子活性，该活性可由转录因子TEAD2维持。对这些肿瘤细胞中的TEAD2进行遗传与药理学抑制，可在体外削弱其促血管生成表型，并在体内抑制肿瘤进展。此外，本研究发现CD109是关键的TEAD2靶基因，可维持活化的JAK-STAT信号通路。综上，本研究结果提示，TEAD2-CD109-JAK/STAT信号轴是潜藏于胰腺癌细胞鳞状亚型相关表观基因组中的潜在治疗易感靶点。实验整体设计：多种PDA细胞系的RNA测序（RNA-seq）谱分析。