This week we profile a recent publication in Science Advances from Dr. Ming Guo’s (pictured) laboratory at Massachusetts Institute of Technology.
Can you provide a brief overview of your lab’s current research focus?
The long-term mission of my lab is to understand how mechanics and biology impact each other in a multicellular system, and together sculpt the evolution of multicellular physiological and pathological processes. With this understanding, we also aim to develop mechanical based methods (for example, via manipulating cell mechanical properties or applying mechanical forces) to interfere multicellular processes, and to regulate disease progression in situ.
To achieve this long-term mission, we are currently developing new tools to probe mechanical properties of cell and extracellular matrix in 3D, aiming to understand how cells regulate their mechanical properties. We are also combining physical and biochemical methods to investigate how cellular physical properties impact biological functions responding to extracellular cues.
What is the significance of the findings in this publication?
In a cancer context, the cells of the surrounding tissue, including fibroblasts, endothelial cells, and immune cells, have altered biological properties compared to their normal state. Hence, a spectrum of impacts of tumor on stroma drives several aspects of cell fate transitions. One predominant cell population in breast is the adipocyte, and its interaction with cancer cells has significant roles in cancer progression. The current understanding attributes their interaction to a biochemical interplay where adipocytes interact with cancer cells through paracrine signals and endocrine signals. However, less is known how the physical stresses generated by tumor affect the cell fate of stroma and adipocytes.
We find that the physical stresses generated by the tumor can induce adipocyte dedifferentiation into a state similar to mesenchymal stem cells (MSCs). Learning from how tumors reprogram the surrounding adipocytes, we demonstrate a physical approach to reprogram adipocytes, and extensively produce MSC-like multipotent stem cell, termed CiDAs (Compression induced Dedifferentiated Adipocytes), in vitro using a pure physical stimulation in a tumor free context. This approach distinguishes itself from other cell reprogramming technologies by its gene editing free manner. The cell resources required to produce CiDAs is adipocytes, a cell type that can be easily isolated from any donors. Thus, this approach enables autologous stem cell transplantation to avoid potential immune response or rejection. As we characterized, the CiDAs have a distinct transcriptome profile, long-term self-renewal, and serial clonogenicity (including osteogenesis, adipogenesis, myogenesis, chondrogenesis, and myofibrogenesis) but do not form teratomas. The unique properties of CiDAs also make them an ideal cell resource for future stem cell therapy and regenerative medicine.
What are the next steps for this research?
- The tumor progression alters biological properties and cell fates of many surrounding tissues or stroma. We anticipate this physical reprogramming effect might also apply to other cell types. We will explore whether there are other cell types that can be programmed by tumor generated physical stresses. Then, we will learn from the tumor microenvironment. We also anticipate use of physical stresses to develop regenerative therapy approaches for different types of tissue, for example, intestine.
- Explore the immune modulation by CiDAs. Both the MSCs and adipocytes were believed to have unique, but distinct effects on immune modulations. Thus, it will be interesting to explore the immune modulation effect of CiDAs. If we reveal the CiDAs activate immune response, we might use CiDAs to enhance the efficiency of immune therapy to cancer treatment. If we reveal a suppression effect of CiDAs on immune response, we can use CiDAs to modulate immune rejection during transplantation, or to treat autoimmune diseases.
If you’d like us to mention your funding sources, please list them.
We acknowledge the support from the National Cancer Institute (grant 1U01CA202123) and the MIT Jeptha H. and Emily V. Wade Award.
