Unraveling cell competition mechanisms in embryonic development using gastruloids, cancer-resistant species, and human 3D models

• Applicant: Joshua David Frenster, Ph.D.
• Subject Area: Cell Biology ; Developmental Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565647416

Cell competition is a key quality control mechanism in early embryonic development, ensuring only the fittest cells contribute to the body plan while suboptimal cells are removed. This non-autonomous process is based on relative fitness differences between viable cells, and results in the apoptosis of lesser fit neighbors, eliminating up to 35% of the cells in the epiblast. Despite its significance for developmental fidelity, the mechanisms by which neighboring cells communicate and compare fitness in mammals remain unclear. Due to its central role in fitness perception, loss of p53 results in the emergence of “supercompetitor” cells, which stand at the apex of cell competition and induce apoptosis even in healthy wild-type (WT) neighbors. While developmental cell competition is restricted to the onset of gastrulation (E6.5 in mice), similar mechanisms reappear in tumorigenesis, either functioning as tumor-suppressive barrier, or being hijacked by cancer cells to eliminate surrounding tissues. I recently established an ESC-based mosaic 3D gastruloid model to study cell competition in mammalian development. Using this system, I demonstrated that introducing just few p53KO cells into WT gastruloids suffices to induce apoptosis in WT neighbors with considerable effect size, independent of previously proposed competition mechanisms and regulated by developmental programs. In my independent research group, I will use this system to identify the pathways and surface proteins mediating developmental cell competition. I will conduct a high-throughput surfaceOme CRISPR screen in mosaic competition gastruloids, complemented by a pharmacological screen and in silico meta-analysis of time-resolved transcriptome data (Aim 1). Further, I will investigate the evolutionary and mechanistic relationship between cell competition and cancer-resistance by generating gastruloids from cancer-resistant species such as naked mole rats and elephants (Aim 2). Finally, I will establish the first human 3D model of cell competition using naïve human gastruloids, examining interactions between WT and viable aneuploid cells to gain insights into error correction mechanisms in human development (Aim 3). This project will advance our understanding of cell-cell communication mechanisms in developmental cell competition, while exploring uncharted avenues into how these processes are regulated in cancer-resistant species and human biology. The findings will have significant implications for both fundamental and translational research, impacting developmental biology, cancer research, and human health.

• DFG Programme: Emmy Noether Independent Junior Research Groups