Research
Maintenance, remodeling, and deterioration of tissue pattern and physiology
Developmental process shapes sophisticated adult tissue pattern. This pattern is maintained over time and also remodeled or deteriorated by intrinsic and extrinsic factors, which has a huge impact on tissue physiology and organismal health. Our overarching goal is to understand the mechanisms underlying the maintenance, remodeling, and deterioration of tissue pattern and physiology. We are particularly interested in elucidating novel 'tissue non-autonomous' mechanisms affecting tissue integrity, metabolism, and malignant transformation by utilizing Drosophila genetics, cell biology, and biochemistry.
Communication between epithelial tumors and host tissues
Growing evidence highlights the importance of interorgan communication in the maintenance of tissue pattern and physiology. Not supprisingly, tumors also interact with host tissues within and beyond the microenvironment. The well-described manifestation is the wasting syndrome, cancer cachexia, accompanying severe deterioration of muscle. The commonly-accepted notion is that tumors can acquire more nutrients to support their growth by inducing wasting in host tissues. Nevertheless, such metabolic communication has not been proven experimentally. Whether and how remodeling or deterioration of host tissue pattern and physiology remotely affects tumor growth are unclear at this moment.
We have established a unique model of cachexia-like wasting in Drosophila, allowing us to dissect the interactions between tumors and host tissues using the advanced genetic tools available in Drosophila. This model provides us an opportunity to address a number of important yet still elusive questions. We have identified a new tumor-derived wasting factor and addressed why tumors themselves are not wasted away. Currently, we are focusing on addressing the following questions: 1) is tumor growth dependent upon wasting of host tissues? 2) is there a metabolic communication between tumors and host tissues? and 3) what is the molecular basis of such communications?
Kwon Y, Song W, Droujinine IA, Hu Y, Asara JM and Perrimon N. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Developmental Cell (2015) April 6;33:36-46.
Jiae Lee, Katelyn G.-L. Ng, Kenneth M. Dombek, and Young V. Kwon. Tumors Overcome the Action of the wasting factor ImpL2 by Locally Elevating Wnt/Wingless. PNAS (2021)
The genetic basis of cell dissemination
Cancer cells initiate metastasis by disseminating into the circulation. Despite its importance, how transformed cells move out from an intact tissue and enter the circulation is poorly understood, largely due to the lack of a proper in vivo system that allows molecular dissection of the process. In Drosophila, simple genetic manipulation of epithelial tissues can induce hyperplasia or tissue overgrowth—a so called ‘tumor’ in Drosophila—which has led to the discovery of fundamental mechanisms underlying tissue growth and tumorigenesis. These Drosophila tumors also provide a tool to study metastatic behavior, which has allowed the identification of several genetic and environmental factors underling metastatic phenotypes. Nevertheless, it has been largely unknown how these transformed cells migrate from their primary site into the circulation. Recently, we have defined a series of cellular processes and molecular mechanisms required for cell dissemination in Drosophila. Our observations suggest that dissemination of transformed cells could be an opportunistic phenomenon, requiring the mechanosensitive channel Piezo for taking advantage of the opportunity associated with the breach of the tissue integrity. Given the description of the molecular and cellular mechanisms during an actual cell dissemination process, our study underscores the usefulness of Drosophila in deciphering the genetic basis of this invasive process in a native microenvironment.
Using this model, we aim to understand the genetic basis of the cell dissemination process. We are currently conducting a genetic screening to discover novel genes controlling the process. So far, we have uncovered a number of kinases and phosphatases from the screening and plan to continue until we cover the whole genome.
Jiae Lee*, Alejandra Cabrera*, Cecilia Nguyen and Young V. Kwon (*equal contribution) Dissemination of RasV12-trasformed cells requires the mechanosensitive channel Piezo. Nature Communications (2020)
Schematic stages of cell dissemination in vivo
Initially, expression of RasV12 in intestinal stem cells and enteroblasts makes them propagate and, at the same time, move out from the midgut epithelium. These RasV12 cells produce Actin- and Cortactin-rich invasive protrusions at the basal side, which are associated with the breach of the ECM and VM layers (stage 2). Our ex vivo live-imaging results indicate that some of these large invasive blebs/protrusions are released as extracellular vesicles across the VM layer. Finally, RasV12 cells transverse the VM layer via bleb-driven amoeboid movement (stage 3) and complete the transmigration process (stage 4).
Description of invasive protrusions resembling invadopodia, extremely-large extracellular vesicles (ELEVs), and amoeboid movement in Drosophila
Characterization of the cell dissemination process led us to describe new structures, entities, and processes in Drosophila: 1) RasV12-transformed cells produce Actin- and Cortactin-rich protrusions resembling invadopodia observed in cancer cells (white arrowheads), 2) these protrusions grow into big blebs, invading the visceral muscle layer (yellow arrowheads), 3) RasV12-transformed cells generate extracellular vesicles larger than exosomes or microvesicles, which we refer as 'extremly-large extracellular vesicles (ELEVs)', and 4) RasV12-transformed cells use extensive blebbing for transversing the visceral muscle layer. Thus, our observations enable us to use Drosophila as a genetic model for studying these structures, entities and processes in vivo.
Systematic approach to decipher signaling networks
We use systematic approaches, including proteomics, to elucidate the signaling networks controlling tissue pattern and remodeling. We are currently building a comprehensive protein-protein interaction network for alpha-arrestins—the adaptor proteins involved in inhibition of signaling and other cellular processes— in Drosophila and human. We plan to construct additional protein-protein interaction networks for other signaling pathways and expand our scope by adopting new systematic and synthetic approaches.