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

转录可塑性驱动的细胞状态转变促进了肿瘤内的异质性和耐药性。代谢适应支持抗性细胞的生存，表观遗传调节剂是基因表达控制的关键守门人，从而调节细胞状态的转变。胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）是最具治疗抗性的实体肿瘤之一，不同的治疗方法可诱导表型转换，从而促进药物诱导的细胞状态转变。然而，对肿瘤内调节细胞死亡途径和表型相互转换以维持PDAC耐药的关键表观遗传驱动因素和信号通路的清晰理解尚不清楚。同样，调控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不是很清楚。在CRU的第一个资助期，我们观察到PDAC对MEK抑制的早期和适应性抗性表型都与显着的表观遗传和代谢适应相关。meki耐药表型的特征是替代FGFR1/AKT信号的表观遗传激活，以及调控细胞死亡和高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也有类似的观察结果。因此，这些观察结果可能构成癌症总体适应机制和外代谢依赖性，驱动癌症靶向治疗耐药。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方面的问题。具体来说，我们想了解FGFR1/AKT的表观遗传激活和代谢适应是否交织在一起，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之间的关系。我们希望了解meki敏感群体和meki抗性群体之间调节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变的影响及其潜在的表观遗传驱动因素。这将允许识别和临床前验证的协同分子靶向已确定的依赖性。为了达到这些目标，CRU内部的概念和机制框架将非常有益。在CRU内，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械专业知识。我们将为CRU的其他成员提供全面的模型系统、生物信息学和代谢专业知识，并将提供其他实体结果的交叉验证。所有这些都将共同努力，在耐药细胞中找到可靶向的外代谢依赖性，并为设计概念验证临床试验奠定基础。

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.