A special puppeteer holds the strings to liver cells’ identity
Scientists at EMBL and DKFZ have discovered how cells in the liver maintain their identity and avoid becoming tumour cells
Scientists at EMBL and DKFZ discovered a protein, called PROX1, in liver cells that preserves cell identity and prevents them from becoming tumour cells. In a way, PROX1 acts as a puppeteer controlling liver cell fate by preventing them from taking different paths. Here, a puppeteer’s hands control the mountain ridges in Waddington’s illustration of cell fate commitment, adding another detail to our understanding of cell fate. Credit: Daniela Velasco/EMBL
Summary
A new collaborative study by Judith Zaugg and Moritz Mall, Group Leaders at EMBL and DKFZ respectively, led to the identification of a crucial protein, called PROX1, able to maintain liver cell identity and prevent liver cancer formation.
In liver cancer patient samples, higher levels of PROX1 correlate with better prognosis and longer survival.
In preclinical liver cancer mouse models, PROX1 can halt cancer formation and slow down cancer progression.
This work paves the way to developing novel therapeutic strategies for liver cancer and to discovering similar factors in other cell and cancer types.
A collaboration between EMBL Heidelberg and the German Cancer Research Centre (DKFZ) led to the identification of a special protein in liver cells, which helps maintain the cells’ identity throughout their lifetime and prevents cancer formation. In some ways, this protein acts as a puppeteer pulling the strings that control the fate of liver cells.
The preservation of cell identity is crucial for the well-being and functioning of our bodies. Judith Zaugg, EMBL Group Leader and senior author of this study, now also affiliated with the University of Basel, said: “You would think a cell maintains its identity only through passive processes, while all its activity is dedicated to performing its different functions. Now we know that a cell also needs to actively work to preserve its identity.”
All our cells contain the same DNA, the molecule carrying the code of life. However, each cell only needs to decipher a portion of it to define its identity and fulfil its purpose. Therefore, cells have measures in place to make sure that unwanted instructions in the DNA are not read. Errors in these mechanisms can result in cell malfunction, death, and transformation into cancer cells. Moritz Mall, DKFZ Group Leader and senior author of this study, said: “Our goal is to understand how cells regulate their fate in normal development, and how this gets disrupted in disease.”
A famous illustration of cell fate commitment, first drawn by British scientist Conrad Waddington in 1957, shows a landscape with mountain peaks and valleys. From the top of a mountain, a marble ball representing a stem cell – a cell with the potential to transform into any other cell – can take multiple paths leading to different valleys, or cell fates. Several factors, many of which are already known, define the various roads by carving the valleys in between the mountains, thus dictating which direction a certain cell will go. However, how the mountain ridges are raised so that cells stay on track and do not take alternative paths has long been unclear.
In this project, Aryan Kamal and Bryce Lim, at the time doctoral researchers in Zaugg’s and Mall’s groups and co-first authors of this study, identified a special protein, called PROX1, in liver cells able to maintain their fate and prevent them from transforming into other cells, including cancer cells. To do so, PROX1 silences many factors that activate alternative cell fates thereby blocking all the other paths. In a way, looking at Waddington’s illustration of cell fate, PROX1 acts as a puppeteer pulling several strings to elevate the mountain ridges between different valleys. As a consequence, liver cells stay on the right track.
By combining the computational skills of the Zaugg Group with the disease modelling tools of the Mall lab, the researchers were able to thoroughly study the function and impact of PROX1 in both liver cancer patient samples and preclinical mouse models.
In liver cancer patient samples, they observed that with more abundant PROX1, prognosis was better, and patients survived longer.
This promising observation encouraged them to investigate the therapeutic potential of PROX1 in preclinical mouse models. Mice developing liver cancer in the presence of PROX1 showed less aggressive tumours and longer survival than mice developing liver cancer without PROX1, indicating that PROX1 impeded tumour formation. Furthermore, inducing PROX1 after tumours had already developed also slowed tumour progression.
To further demonstrate the importance of PROX1, Zaugg and Mall looked at a peculiar feature of liver cells. The liver is a special organ, in that it can regenerate after an injury, such as after drinking alcohol or being exposed to food toxins. The researchers observed that PROX1 was essential for liver regeneration and recovery in mice experiencing a liver injury.
Overall, by identifying PROX1 as an important factor able to halt liver cancer formation and progression, and favour liver regeneration, the researchers paved the way to developing novel therapies for liver cancer patients.
“Our pioneering study can open interesting, conceptually new views on cancer therapies,” Zaugg said.
The interesting aspect of this discovery does not end here. In a previous study, Mall’s group identified another protein with a similar function in neurons. Thus, the new insights on PROX1’s role expand this concept from the brain to the liver and possibly to other tissues.
“These factors might exist in other cell types and other cancers,” Mall said. “If we learn how to target them with gene therapy and other approaches to regulate their expression, we might achieve something that we can now only dream of.”
The exciting results of this successful collaboration between EMBL and DKFZ are also a tribute to the collaborative aspect of science. Zaugg and Mall began their PhDs together at EMBL and have been collaborating since they both started their own research groups.
“This is an amazing example of how the EMBL spirit can carry through the life of a researcher and enable exciting new discoveries,” Mall said – to which Zaugg added, “And there might be more coming up.”
