- ASSOCIATE DEAN OF THE GRADUATE SCHOOL OF BIOMEDICAL SCIENCES
- PROFESSOR Developmental and Regenerative Biology
- PROFESSOR Oncological Sciences
- PROFESSOR Ophthalmology
- Ross L. Cagan, PhD, is Professor of the Department of Developmental and Regenerative Biology, Associate Dean for the Graduate School of Biomedical Sciences, and Director of the Center for Personalized Cancer Therapeutics. He is also Editor-in-Chief of Disease Models and Mechanisms and co-founder and Boar Member of Medros Inc.
Dr. Cagan's laboratory focuses on the use of Drosophila to address disease mechanisms and therapeutics, primarily for cancer and diabetes. In cancer, their work helped validate vandetanib as a therapeutic for Medullary Thyroid Carcinoma, combined Drosophila genetics and medicinal chemistry to develop a new generation of lead compounds that emphasize "balanced polypharmacology", and identified novel mechanisms that direct transformed cells into the first steps towards metastasis. Regarding diabetes, his laboratory has identified mechanisms that direct diabetic cardiomyopathy and nephropathy as well as a new network through which diabetic patients are at heightened risk for aggressive tumors.
Combining these basic research approaches, Dr. Cagan has established the Center for Personalized Cancer Therapeutics, in which new tools including 'personalized Drosophila avatars' are developed and used to screen for personalized drug cocktails. Working with co-directors Marshall Posner and Eric Schadt, the CPCT is designed to identify drug combinations that best address the tumor's complexities. For more information, please visit the Cagan Laboratory website.
For more information, please visit the Cagan Laboratory website.
Patterning of the Drosophila eye
One of the fundamental interests of the laboratory is exploration of epithelial patterning. How does an initially random collection of undifferentiated cells mature into a precise and functional organized epithelium? The developing Drosophila eye is an elegant model for studying epithelial patterning and, incidentally, is one of nature's most beautiful structures (Figure). We have used genetics, biochemistry, histology, laser ablation studies, disc culturing, microarrays, and computational modeling to explore how these epithelial cells move within the epithelium to find their final positions.
Figure 5. The adult fly eye.
Mutations in the transmembrane adhesion proteins Rst and Hbs lead to a failure of IPCs to move into their correct niches. We find that their adhesion to each other across neighboring cells provides the ‘attraction’ that helps move cells to their proper niches. This involves adhesion but also actin cytoskeleton rearrangement, and we have identified many factors that mediate this cytoplasmic process. The result is dynamic cell movement, important for eye patterning; similar mechanisms may be at play in our cancer metastasis models. As we further explore the developing fly eye, we are beginning to integrate adhesion, signal transduction, and cell biology to achieve a more complete and useful understanding of the mechanisms that direct epithelial patterning.
For more information, please visit the Cagan Laboratory website.
A different approach to disease
Cancer has proven a difficult disease to achieve significant long-term advances in patient survival; improvements in survival are often measured in months. Diabetes has not fared much better. My laboratory has undertaken a genetic and drug screening approach targeting cancer and diabetes utilizing the fruitfly Drosophila. We use the advantages of the fly to take a whole animal, integrated approach to disease: genes and drugs identified in flies are tested in rodents with the goal of clinical trials; sequencing and histological data from humans are then brought back to our fly models to allow us to develop increasingly sophisticated fly models.
Cancer Models: My laboratory has developed Drosophila cancer models for colorectal, breast, lung, and (Ret-based) thyroid tumors, phenocopying many aspects of their human counterparts (e.g., Figure). We utilize genetic, molecular, and computational approaches to explore these diseases at a systems level, within the context of the whole animal.
Figure 1. Adult fly eyes, Left; a normal eye, Right; An eye expressing an oncogenic (cancer-causing) form of Ret. The eye is small and 'rough', reflecting defects in the underlying epithelium.
Metastasis: Working in flies, we demonstrated that activating Src sets up a ‘metastatic boundary’ of cells that migrate away specifically from the tumor's edge (Figure); we have implicated multiple factors in this ‘metastasis’. Working with pathologists, we established evidence from histological sections that human solid tumors share many of these same molecular/spatial aspects present in our fly models (Figure). Based on this work we have proposed a model of metastasis that emphasizes local cell-cell interactions within the epithelium, a model we continue to explore.
Figure 2. Fly Src-mediated ‘tumors’ in the wing epithelium (left) lose E-cadherin (green) at tumor edges (brackets); human Squamous Cell Carcinomas (right) share this loss of E-cadherin (brown).
Diabetes: Working with Tom Baranski's and Rolf Bodmer’s laboratories, we have created a fly model of type 2 diabetes. Flies placed on a high-carbohydrate diet demonstrate a broad range of defects observed in human diabetics including hyperglycemia, hyperlipidemia, insulin resistance, and obesity. We have focused on perhaps the two most serious aspects of diabetes, heart failure and kidney failure (Figure). Recently, we also identified the pathways by which diabetic patients are at greater risk for specific cancer types. Our goal is an effective whole-animal approach to understanding and treating diabetes and associated diseases.
Figure 3. Fly heart (center, green) and fly kidney ‘nephrocyte’ (red). These fail on a high sugar diet.
Drug Development: My laboratory has developed a novel method of high-throughput drug screening using our fly models, robotics, and compound libraries. Through our feeding paradigms, we provided whole animal validation (Figure) that helped identify ZD6474 as a useful tool for treating Medullary Thyroid Carcinoma patients; the compound is now the first approved chemotherapeutic for MTC. More recently working with Kevan Shokat’s laboratory, we combined fly genetics and medicinal chemistry to develop a novel class of compounds that emphasize whole animal “rational polypharmacology”. By identifying and better hitting “targets” while removing activity against “anti-targets”, our approach has shown the ability to develop drugs with strongly improved efficacy and reduced whole animal toxicity.