Workshop 1: Visualizing and Modeling Cellular and SubCellular Phenomena
Cell motility is coordinated by an intricate network of interacting proteins and lipids, that transduce signals into cytoskeletal reorganization, cell shape changes, and locomotion. Here I will survey some mathematical modeling that addresses both normal and aberrant cell motility. I will describe efforts in my group to construct and analyse mathematical models for proteins (such as Rho family GTPases) and lipids (such as phosphoinositides), their feedbacks and their effects on protrusion and contraction of the cell front and rear, as well as cell shape. The role of the cytoskeleton and its actin-associated proteins (e.g. cofilin) will be mentioned. I will describe how several projects on cell polarity and GTPase spatial patterns have contributed to some insights into cell motility.
Modeling the regulation of cofilin and actin based protrusion in invasive tumor cells
During the metastasis, tumor cells move through the primary tumor and enter blood vessels (1). Tumor cell motility has been previously investigated in details in vitro and the signaling pathways which control locomotion in 2D or invadopodia formation, which results in extracellular matrix degradation and penetration, have been dissected (2,3). However, the conditions for the onset of such movements in vivo are not yet fully understood. Using multiphoton-based intravital microscopy we previously reported that the vicinity of macrophages (4) or blood vessels (5) is essential for tumor cell locomotion to occur in primary breast tumors. Yet other studies have demonstrated that the changes in stiffness (6) and architecture (7) of extracellular matrix may lead to increased motility and subsequently, metastasis. However, each of these factors has been studied separately and no attention was given to their combinatorial effect. Here we show that multiparametric, systems-level analysis is vital to predict tumor cell motility-related behaviors in vivo. Our analysis reveals the context in which invadopodia or tumor cell locomotion appear in vivo. Direct link was found between invadopodia number and lung metastasis. To predict invadopodium formation, which leads to intravasation, we conclude, microenvironmental conditions must be studied in concert rather than in isolation. Furthermore, future development of diagnostic markers for early metastasis will most likely necessitate such multiparametric analyses
Live microscopy allows observing rapidly moving samples, such as whole embryos during their development. Motion can be local (e.g. individual cells migrating, dividing, or contracting) or more global (e.g. induced by tissue growth or organ function). When the observed motion is induced by more than a single process or occurs at multiple temporal and spatial scales, subtler motions and events are often hidden among more prominent, but unrelated, motions patterns. For example, within the beating and developing heart, cells undergo both rapid, periodic motions as the heart contracts to pump blood and also slower motions as the cells rearrange during maturation of the heart. In this talk, I will discuss in vivo image acquisition, processing, and analysis tools that we developed to digitally document both the morphogenesis and the function of the developing heart. Specifically, I will present our strategy to capture and integrate heterogeneous data acquired with multiple microscopy modalities (including fluorescence microscopy and optical coherence tomography), at multiple temporal and spatial scales (from milliseconds to hours and from single cells to entire organs, respectively), and in multiple dimensions. This allowed us to observe cellular division on the surface of the beating heart without the need to ever slow or stop it, demonstrating the possibility of disentangling complex motion patterns through customized imaging and digital post-processing strategies.
NAD+ biosynthesis ameliorates muscular dystrophy in zebrafish