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

• Applicant: Professor Dr. Jens T. Siveke
• Subject Area: Dermatology ; Gastroenterology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257

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.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 337: Phenotypic Therapy and Immune Escape in Cancer (PhenoTImE): pre-clinical and translational advance of the CRU 337
• International Connection: USA
• Cooperation Partner: Steven A. Johnson, Ph.D.