UCLA

Metastasis is a physical process in which cells are required to deform through narrow gaps and generate forces as they invade surrounding tissues. Understanding the relationship between invasion and cell physical properties, such as deformability and contractility, can impart knowledge that guides the development of new therapeutics, yet the physical properties of pancreatic cancer cells are still poorly understood. In many cancers, more invasive cells are more deformable than less invasive cells. However, using atomic force microscopy, I discovered that more invasive pancreatic ductal adenocarcinoma (PDAC) cells tend to have a higher Young’s modulus, indicating that they are stiffer. This finding challenges the oversimplified notion that decreased cell stiffness is a hallmark of cancer invasion. To gain a more complete understanding of why stiffer PDAC cells are more invasive, I examine the ability of PDAC cells to actively generate forces through actomyosin contractility and actin polymerization, as both processes have been associated with cancer cell invasion and stiffness. Using pharmacologic inhibitors, I determined that actomyosin contractility (inhibited with blebbistatin), as well as the polymerization of actin by Arp2/3 (inhibited with CK-666) and formin (inhibited with SMIFH2), contribute to the stiffness of PDAC cells. Interestingly, I observe that these inhibitors are cell line specific, indicating that different PDAC cell lines may rely on different modes of motility to invade the extracellular matrix. In addition, using measurements of cell physical phenotypes obtained by microfluidic quantitative deformability cytometry, my collaborators and I define a minimal set of physical phenotypes that can predict PDAC cell invasion. Taken together, my dissertation work provides valuable insight into the physical mechanisms of cancer cell invasion, and establishes a physical model that can predict cell invasion based on single-cell physical phenotypes including cell stiffness. My results provide the foundation for future studies into the relationship between cell physical properties and the tumor microenvironment, which undergoes substantial physical changes throughout PDAC progression.