Clocking in on colorectal cancer: unraveling the role of circadian clocks in CRC progression using single cell profiling and next-generation organoids.

• Applicant: Dr. Anna-Marie Finger
• Subject Area: Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536902448

Colorectal cancer (CRC), a malignant tumor of the large intestine, is among the top 3 new cancer cases and cancer deaths worldwide. While primary CRC shows good prognosis, metastatic CRC is a highly complex and systemic disease with dismal 5-year survival rates. Although improved clinical routine has led to a decline of CRC related cancer deaths in the elderly, CRC incidence and metastases are currently on the rise in younger adults (<50 years of age). While the cause of early-onset disease is unknown, lifestyle choices and social determinants likely contribute. Recently, circadian disruption, perturbation of endogenous circadian clocks, has been identified as independent risk factor for cancer and classified as a probable carcinogen. Circadian disruption, due to artificial lighting, shiftwork, and international travel, is common in our modern 24/7 society. Moreover, increasing evidence points towards the mechanistic involvement of endogenous circadian clocks in CRC development and progression, providing unexplored opportunities to better understand and treat this disease. Therefore, this proposal aims to unravel the role of circadian clocks in CRC progression using single cell profiling and next-generation organoids. We will study primary and metastatic colorectal tumors and matched normal tissue on single cell level to identify rhythmically regulated, multicellular interaction networks underlying CRC progression. We will then develop next-generation organoids, i.e. 3D co-cultures of patient derived epithelial organoids with other components of the tumor microenvironment (TME), to model such interactions between immune, stromal, and malignant cells. Lastly, using our 3D human tumor platform, we will perform intervention studies to ascertain the mechanistic connection between endogenous circadian clocks and CRC progression. Overall, we expect the proposed project to yield novel insight into CRC biology with important implications for young onset cancer prevention and therapy.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Jeroen Roose, Ph.D.