Institute of Medical Psychology and Department of Molecular Biology

Project description:

The circadian clock coordinates daily rhythms in cellular metabolism, proliferation and stress responses—processes that are profoundly altered during tumorigenesis. However, whether circadian function is maintained in tumors remains controversial and may depend on the tumor type, oncogenic context, cellular state and surrounding microenvironment. Our previous work based on a medium-throughput real-time bioluminescence recording of circadian reporters revealed that most tested primary mouse and human pancreatic ductal adenocarcinoma (PDAC) cell cultures retain functional cell-intrinsic circadian rhythms, independently of their oncogenic driver mutations. We further demonstrated, for the first time, that tumor-cell-intrinsic circadian rhythms are preserved within PDAC tissue in vivo.

Building on these findings, the PhD candidate will investigate the molecular mechanisms underlying circadian function in PDAC and characterize how and which cellular processes are regulated by the tumor-intrinsic clock. Functional and non-functional PDAC oscillators will be compared using temporal transcriptomic, proteomic and chromatin-based (i.e. ChIPSeq) approaches to identify clock-controlled pathways and the mechanisms responsible for their rhythmic regulation. Selected circadian outputs will subsequently be genetically or pharmacologically perturbed to establish their contribution to tumor-cell fitness, proliferation and treatment response. By examining therapeutic sensitivity across the circadian cycle, the project will determine whether rhythmic changes in PDAC cell state generate specific temporal windows of vulnerability that can be exploited to improve treatment efficacy.