Evan Gerard I, Hah Nasun, Littlewood Trevor D, Sodir Nicole M, Campos Tania, Downes Michael, Evans Ronald M
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California.
Clin Cancer Res. 2017 Apr 1;23(7):1647-1655. doi: 10.1158/1078-0432.CCR-16-3275.
The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer-driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease.
胰腺导管腺癌（PDAC）的“特征”包括增殖性、侵袭性和转移性肿瘤细胞，以及由成纤维细胞、胰腺星状细胞、细胞外基质和免疫细胞组成的相关致密纤维组织增生。致癌激活的胰腺上皮及其相关基质必然相互依赖，由此产生的炎症和免疫抑制微环境对PDAC的进展和维持有很大影响。胰腺特有的肿瘤表型是癌基因操控胰腺固有再生程序的结果，这是一种由离散的超级增强子网络调控的组织特异性修复机制。超级增强子被定义为包含多个增强子簇的基因组区域，在细胞/组织特化、特性维持方面发挥关键作用。因此，干扰这种由超级增强子驱动的修复网络对肿瘤组织和正常胰腺组织的破坏作用将有显著差异。直接或间接抑制调控表观遗传状态和完整性过程的新型药物，包括那些由组蛋白去乙酰化酶、组蛋白甲基转移酶和羟化酶、DNA甲基转移酶、各种代谢酶以及溴结构域和额外末端基序蛋白驱动的过程，已证明在治疗包括PDAC在内的多种肿瘤类型中破坏超级增强子依赖性转录的可行性。胰腺腺癌依赖于内在的超级增强子转录机制这一观点表明，这种易损性有可能作为针对这种难治性疾病的新疗法的靶点。
