Synthesizing regenerative potential and preventing cancer risk by spatio-temporal control of cellular plasticity.

• Applicant: Dr. Johnny Kim
• Subject Area: Cell Biology ; Developmental Biology ; Hematology, Oncology ; Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496710327

Specific early zygotic and embryonic genes, which govern toti- and pluripotency during development, respectively, can spontaneously initiate tumor formation by plasticity gain, when aberrantly activated in regenerating SCs. If the expression of early zygotic and/or embryonic genes would be controlled, we might endow regenerative properties - including cellular plasticity - to cells that normally cannot regenerate. Embarking on this paradigm, we have engineered means to enable heart regeneration through reversible reprogramming of post-mitotic adult cardiomyocytes in vivo. The heart is normally not only devoid of regenerative capacity but tumors also virtually never develop in the heart. Strikingly, if embryonic gene expression is sustained, these mice develop cardiomyocyte-derived heart tumors with 100% penetrance providing the first and only model of heart cancer. Fundamentally, this means that it is possible to synthesize re-entry of post-mitotic cells into the cell cycle by directed (epi-)genetic conversion, opening entirely new perspectives on the cellular origins of cancers and their therapeutic targeting as well as synthetic means of cellular transformation and tissue regeneration. This project has the following objectives: Objective 1. To investigate how zygotic and/or embryonic genes epigenetically reprogram post-mitotic cardiomyocytes to a mitosis-competent state. Objective 2. To investigate how zygotic and/or embryonic genes redirect the epigenome of a failing stem cell population back to a regenerative-competent state. Objective 3. To investigate if and how zygotic and/or embryonic genes redirect the epigenome of a cancer prone stem cell population to a cancer resistant state.

• DFG Programme: Research Grants