Unravelling cancer cell states to develop precision therapies for colorectal cancer

• Applicant: Dr. Kimberly Hartl
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564092005

Colorectal cancer is the second most deadly cancer worldwide and accounts to nearly 1 million deaths every year. Despite large efforts to advance treatment options, resistance to therapy and recurrence remain common, contributing to the high mortality rates. Colorectal cancer develops through a mutational cascade in which genetic alterations accumulate in cells of the colon epithelium in which lesions progress from adenomas to malignant carcinomas. Until recently, malignant properties of the arising tumors have been mainly attributed to a subpopulation of tumor stem cells, the so-called Lgr5+ cancer stem cells, but recent findings challenged this dogma when a second, Lgr5- population was found that could sustain tumor growth as well. Conventional therapy mainly targets the Lgr5+ cancer stem cell population, but cancer cells can dynamically adapt to this treatment (“reprogram”) to survive. It now becomes evident that cancer stem cells can dynamically shift their identity between the different cell states (e.g. Lgr5+ to Lgr5- and back) and by this allow for therapy resistance. This evidence suggests the necessity to target the different cell states simultaneously to eradicate all tumor cells, however we still lack a detailed understanding of the characteristics of the different states and putative hybrid states, as well as of their reprogramming dynamics and possible treatment targets. This is why in this study I aim at characterizing the different cancer stem cell states in depth, to mechanistically understand their interdependence and to identify possible drug targets to eradicate them. To achieve this, I will use modern 3D cell culture systems from primary cells (organoids) that allow me to i) model colorectal cancer progression and the impact of mutations on cell states ii) visually track cell state changes via reporter systems iii) verify my findings on patient derived samples and perform drug screenings. In a later step of the project, I will use combination treatments of newly identified pharmaceuticals and established standard-of-care treatment in order to target the different cell states simultaneously. The most promising combination treatment will be validated in animal models to verify their efficacy. In this project, I expect to establish the mechanistic foundation for designing effective combination therapies with enduring impact to significantly improve colorectal cancer treatment options and via this patient outcomes.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ernesto Guccione