/ News, Research
PROX1 Maintains Hepatocyte Identity and Prevents Liver Cancer by Suppressing Cell Fate Plasticity (Zaugg Lab)
A groundbreaking study co-led by postdoctoral researcher Aryan Kamal of the Zaugg lab, affiliated with the EMBL in Heidelberg and our Department of Biomedicine, in collaboration with Bryce Lim in Moritz Mall’s labat the German Cancer Research Center, has shed light on a critical mechanism governing cell identity and plasticity.
Cell fate plasticity, a process essential for development but often dysregulated in cancer, is tightly controlled by a balance of gene activation and repression. By developing a computational screen, the researchers identified a group of proteins, termed safeguard repressors, that actively suppress unwanted cell fate transitions in 18 different cell types. Focusing on the liver, they experimentally validated hepatocyte-specific repressors and identified Prospero Homeobox Protein 1 (PROX1) as a key player. PROX1 directly represses genes associated with alternative cell fates, thereby stabilizing hepatocyte identity.
In in vivo models, PROX1 was found to be essential for effective liver regeneration and blocked tumor formation and progression. Strikingly, depletion of PROX1 in vivo led to loss of hepatocyte fate and promoted the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression of PROX1 facilitated the reverse transition.
These findings strongly support the role of PROX1 as a hepatocyte-specific safeguard repressor and revealed a new mechanism for maintaining cell identity via active repression of alternative cell fates. We congratulate the Zaugg lab and their co-authors for this groundbreaking discovery, which has the potential to transform our understanding of cellular plasticity and open new avenues for cancer and regenerative medicine therapies.