Metastasis, the ability of cancer to spread throughout the body, is the primary cause of cancer-related deaths. This process involves cancer cells breaking away from the primary tumor and traveling to distant parts of the body. To better understand how cells separate from a tissue, scientists at Memorial Sloan Kettering Cancer Center (MSK) focused on embryonic development, where cells move around significantly.
The lab of Anna-Katerina “Kat” Hadjantonakis, Ph.D., conducted new research using high-resolution, time-lapse microscopy to better understand the epithelial-to-mesenchymal transition (EMT) process. EMT is a hallmark of cancer metastasis, and studying the process in a developmental context can help shed light on its role in cancer. The study shows, in detail, how cells initiate this breakaway movement, including identifying key proteins involved in the process.
Dr. Hadjantonakis, Chair of the Developmental Biology Program at MSK, explains that cancer cells often hijack developmental programs to spread throughout the body. Therefore, having a developmental biology research program within a cancer center like MSK makes sense. Understanding how these programs work in healthy cells can provide insight into what happens in disease. The findings were published in eLife on May 10.
Overcoming challenges to study cell movement during embryo development
Over the course of more than five years, Alexandre Francou, Ph.D., a senior research scientist, has been dedicated to understanding how cells behave as they detach from their neighboring cells and move within the embryo. This has been a challenging task, as Dr. Francou has had to overcome various technical obstacles. He is the first author of a study published in eLife, and was previously a research fellow in the lab of Kathryn V. Anderson, Ph.D., who was a co-author of the study and chaired the Developmental Biology Program until her passing in 2020.
Dr. Francou’s research focused on the process of epithelial-mesenchymal transition (EMT), during which epithelial cells, such as those that line the internal and external surfaces of our bodies, undergo transformation into mesenchymal cells. The latter are mobile cells that play a crucial role in the development of complex structures, as well as wound healing and tissue regeneration.
For epithelial cells to become more mobile, they need to lose certain properties, such as the ability to adhere closely to their neighboring cells, which is important for creating continuous surfaces like skin. Additionally, these cells have a defined orientation, known as polarity, which allows them to interact with the external environment on one side, while being anchored to underlying tissue on the opposite, inward-facing side.
The EMT process that the researchers were investigating occurs during the early stages of an embryo’s development, specifically during gastrulation, when cells from an epithelial layer detach and move around the embryo to form different organs and tissues. To study this process, the researchers used time-lapse movies of mouse embryos, which more closely resemble human development than simpler models like fruit fly and chicken embryos.
However, the mouse model presented its own challenges, as the cells undergoing EMT were internal and obscured by several layers of cells, making them difficult to access for imaging. To overcome this, Dr. Francou used genetically engineered mouse models that had fluorescent probes attached to proteins-of-interest at the cell membrane, which allowed for visualization and analysis of the changes in the cells.
The study shed new light on the molecular mechanisms involved in the EMT process in mammals and found that cells contract in a series of ratchet-like pulses to break away from their tissue of origin. The researchers also identified two groups of proteins that play critical roles in the contraction of cells, enabling their escape from the tissue.
Moreover, the study highlighted similarities and differences between the EMT process in mammalian embryos and invertebrate fruit fly embryo models. Overall, the research contributes to a better understanding of EMT and its role in development and cancer metastasis.