Adaptive epigenetic and metabolic regulation of redox circuits in drug persisting pancreatic cancer cells

药物持久性胰腺癌细胞中氧化还原回路的适应性表观遗传和代谢调节

• 批准号: 418179795
• 负责人: Professor Dr. Jens T. Siveke
• 金额: --
• 依托单位: Department of Gastroenterology and Hepatology
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/418179795?language=en
• 关键词: Adaptive; epigenetic; metabolic; regulation; redox

Transcriptional plasticity-driven cell state transitions fuel intratumoral heterogeneity and drug resistance. Metabolic adaptation supports the survival of resistant cells and epigenetic modulators are key gatekeepers of gene expression control, thereby regulating cell state transition. In pancreatic ductal adenocarcinoma (PDAC), one if not the most therapy-resistant solid tumor entity, various therapeutic approaches induce phenotype switches, thereby fueling drug-induced cell state transitions. A clear understanding of the key epigenetic drivers and signaling cues modulating regulated cell death pathways and phenotype interconversions within tumors to sustain drug resistance in PDAC is however missing. Similarly, the epigenetic control hubs regulating the metabolic adaptation of both early and adaptive resistance phenotypes are not well understood.During the first funding period of the CRU, we observed that both early and adaptive resistance phenotypes to MEK inhibition in PDAC are associated with significant epigenetic and metabolic adaptations. MEKi-resistant phenotypes were characterized by epigenetic activation of alternative FGFR1/AKT signaling as well as downregulation of regulated cell death and high ROS defense activities. Similar observations have equally been made in other cancer entities within the CRU such as melanoma and glioblastoma. These observations may thus constitute cancer-overarching adaptive mechanisms and epi-metabolic dependencies driving targeted therapy resistance in cancer. However, successful targeting will require an in-depth understanding of the molecular control hubs and we plan to address these aspects during the second funding period. Specifically, we would like to understand if epigenetic activation of FGFR1/AKT and metabolic adaptations are interwoven events and how this relates to regulation of cell death and potential microenvironmental and immune-regulatory consequences. We would like to understand the epigenetic control hubs modulating redox balance between MEKi-sensitive and MEKi-resistant populations. We would like to investigate the impact of the tumor microenvironment on tumor cell state transitions and the underlying epigenetic drivers. This will allow for the identification and preclinical validation of synergistic molecules targeting the identified dependencies. To arrive at these objectives, the conceptual and mechanistic framework within the CRU will be highly beneficial.Within the CRU, our subproject will greatly benefit from the immunological and bioinformatics as well as mechanistic expertise of other groups. We will equally contribute our comprehensive model systems, bioinformatic and metabolic expertise to other members of the CRU and will offer cross-validation of results from other entities. All of these will work together to find targetable epi-metabolic dependencies in drug resistant cells and lay the ground work for the design of proof-of-concept clinical trials.

转录可塑性驱动的细胞状态转换促进肿瘤内异质性和耐药性。代谢适应支持抗性细胞的存活，并且表观遗传调节剂是基因表达控制的关键守门人，从而调节细胞状态转变。在胰腺导管腺癌（PDAC）中，即使不是最耐治疗的实体瘤实体，也是一种，各种治疗方法诱导表型转换，从而促进药物诱导的细胞状态转变。然而，缺乏对调节调节细胞死亡途径和肿瘤内表型相互转化以维持PDAC耐药性的关键表观遗传驱动因素和信号传导线索的清晰理解。同样，调节早期和适应性抗性表型的代谢适应的表观遗传控制中心也没有很好地理解。在CRU的第一个资助期间，我们观察到，PDAC中对MEK抑制的早期和适应性抗性表型与显著的表观遗传和代谢适应相关。MEKi抗性表型的特征在于替代FGFR 1/AKT信号传导的表观遗传激活以及受调节的细胞死亡和高ROS防御活性的下调。在CRU内的其他癌症实体（如黑色素瘤和胶质母细胞瘤）中同样进行了类似的观察。因此，这些观察结果可能构成癌症总体适应机制和表观代谢依赖性，从而驱动癌症的靶向治疗耐药性。然而，成功的靶向将需要深入了解分子控制中心，我们计划在第二个资助期内解决这些问题。具体来说，我们想了解FGFR 1/AKT的表观遗传激活和代谢适应是否是交织在一起的事件，以及这与细胞死亡的调节和潜在的微环境和免疫调节后果的关系。我们想了解调节MEKi敏感和MEKi抗性群体之间氧化还原平衡的表观遗传控制中心。我们希望研究肿瘤微环境对肿瘤细胞状态转换的影响以及潜在的表观遗传驱动因素。这将允许鉴定和临床前验证靶向所鉴定的依赖性的协同分子。为了达到这些目标，CRU内部的概念和机制框架将是非常有益的。在CRU内部，我们的子项目将极大地受益于免疫学和生物信息学以及其他小组的机制专业知识。我们同样将向CRU的其他成员贡献我们全面的模型系统、生物信息学和代谢专业知识，并将提供对其他实体结果的交叉验证。所有这些将共同努力，在耐药细胞中找到有针对性的表观代谢依赖性，并为设计概念验证临床试验奠定基础。