Sherman Mara H, Yu Ruth T, Tseng Tiffany W, Sousa Cristovao M, Liu Sihao, Truitt Morgan L, He Nanhai, Ding Ning, Liddle Christopher, Atkins Annette R, Leblanc Mathias, Collisson Eric A, Asara John M, Kimmelman Alec C, Downes Michael, Evans Ronald M
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1129-1134. doi: 10.1073/pnas.1620164114. Epub 2017 Jan 17.
A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular "AND-gate" such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.
纤维炎性基质反应与致癌信号协同作用，影响胰腺导管腺癌（PDAC）的起始、进展和治疗结果，然而这种相互作用的机制仍知之甚少。在这里，我们表明基质信号在癌细胞中引发适应性反应，包括快速动员一个与加速生长相关的转录网络，以及代谢组改变的合成代谢变化。体外基质诱导的变化与先前在体内显示受致癌性Kras调控的变化密切重叠，这表明致癌性Kras信号——PDAC的一个标志和关键驱动因素——取决于基质输入。从机制上讲，基质激活的癌细胞在转录增强的基因处显示组蛋白乙酰化广泛增加，这意味着PDAC表观基因组是这些途径之间的假定交汇点和潜在治疗靶点。值得注意的是，抑制表观遗传阅读器的溴结构域和额外末端（BET）家族，特别是含溴结构域蛋白2（BRD2），可阻断体外基质诱导的转录调控和体内肿瘤进展。我们的工作表明存在一种分子“与门”，使得肿瘤激活是突变Kras和基质信号的结果，这为肿瘤微环境在Ras驱动肿瘤的起源和治疗中的作用提供了见解。
