Cell migration plays important roles in diverse physiological processes, such as the movement of germ cells and wiring of the nervous system during embryonic development, trafficking of leukocytes in immune responses, and homing of stem cells to niches. However, deranged migration of cells also underlies the pathogenesis of many diseases including asthma, inflammatory arthritis, atherosclerosis, and metastatic cancers. The goal of our lab is to reveal the molecular mechanisms of the molecular networks governing cell migration and the implications in disease treatment. We are pursuing the following lines of investigation:
Using the model organism Dictyostelium, a social amoeba that shares highly conserved molecular pathways with higher organisms, we have uncovered the requirement for the coupling between two molecular networks during migration: a signaling network (Signal Transduction Excitable Network or STEN), comprising Ras, PI3K, and Rac, and a cytoskeletal network (Cytoskeletal Oscillatory Network or CON) comprising actin and its regulators. The signaling network determines the spatiotemporal generation of protrusions and displays excitable properties such as wave propagation, all-or-none responses, and refractoriness. This excitability allows cells to move efficiently both in the presence and absence of directional cues. In contrast, the cytoskeletal network undergoes fast oscillations to drive small undulation of cell periphery, possibly allowing cells to probe the environment. We will use an interdisciplinary approach involving fluorescent live cell imaging, genetics, and computer modeling to decipher the molecular basis of the systems properties (e.g. excitability and oscillations) of these networks and how they are coupled to each other.
Despite dramatic improvements in the outcome of cancer patients over the past decades, metastatic cancers in general still carry a poor prognosis. Our research on fundamental mechanisms of cell migration opens up an unprecedented opportunity to probe how cancer cells disseminate. We therefore seek to leverage our knowledge and techniques to further investigate the movement of cancer cells in different environments, from in vitro cultures to animal hosts, to obtain a complete picture of cancer behavior at multiple scales. We will also use patient samples to establish the clinical relevance of our experimental findings. Our ultimate goal is to obtain a detailed understanding of the dynamics and functions of the molecular machinery that drives cancer cell motility, and use the information to devise strategies for more effective control of metastasis.
The Ras-PI3K signaling pathway is frequently mutated in human cancers. Our previous research on the crystal structure of PI3Kα revealed how oncogenic mutations may alter the enzymatic activity. More recently, we found spontaneous activation of Ras and PI3K suggestive of excitability of the signaling network across several cell types. Building on these results we seek to understand the role of the Ras-PI3K signaling network from the molecular to the systems level in the context of both normal and cancer cell biology.