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加剧了肿瘤内的异质性和耐药性。代谢适应支持耐药细胞的生存，表观遗传调节器是基因表达调控的关键守门人，从而调节细胞状态转换。在胰腺导管腺癌(PDAC)中，如果不是最耐药的实体瘤，不同的治疗方法会诱导表型转换，从而促进药物诱导的细胞状态转换。然而，对于调控肿瘤内受调控的细胞死亡途径和表型间转换以维持PDAC耐药性的关键表观遗传驱动因素和信号提示尚缺乏明确的认识。同样，调控早期和适应性耐药表型代谢适应的表观遗传控制中枢也没有被很好地理解。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耐药表型都与显著的表观遗传和代谢适应相关。Meki耐药表型的特征是可选择的FGFR1/AKT信号的表观遗传激活，以及调节的细胞死亡和高ROS防御活性的下调。CRU内的其他癌症实体，如黑色素瘤和胶质母细胞瘤，也有类似的观察结果。因此，这些观察结果可能构成癌症主导的适应机制和表观代谢依赖，推动癌症靶向治疗抵抗。然而，成功的靶向将需要对分子控制中心有深入的了解，我们计划在第二个资助期解决这些方面的问题。具体地说，我们想了解FGFR1/AKT的表观遗传激活和代谢适应是否是相互交织的事件，以及这如何与细胞死亡的调节以及潜在的微环境和免疫调节后果有关。我们想要了解调控Meki敏感和耐Meki人群之间氧化还原平衡的表观遗传控制中心。我们想要研究肿瘤微环境对肿瘤细胞状态转变的影响以及潜在的表观遗传学驱动因素。这将允许识别和临床前验证针对已识别的依赖关系的协同分子。为了实现这些目标，CRU内的概念和机械框架将非常有益。在CRU中，我们的子项目将极大地受益于其他小组的免疫学和生物信息学以及机械专业知识。我们将同样向CRU的其他成员贡献我们的全面模型系统、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。所有这些都将共同努力，在耐药细胞中找到有针对性的表观代谢依赖，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.