Cancer Genetics, Developmental Biology, Diabetes
Biophysics and Systems Pharmacology [BSP], Cancer Biology [CAB], Developmental and Stem Cell Biology [DSCB], Genetics and Genomic Sciences [GGS], Neuroscience [NEU]
BA, University of Chicago
PhD, Princeton University
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 “balanced 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.
Figure 4. Feeding flies the chemical kinase inhibitor ZD6474 led to rescue of the Ret-mediated tumorigenic phenotype.
Center for Personalized Cancer Therapeutics:Tying these approaches together, we have opened the Center for Personalized Cancer Therapeutics. Working with co-directors Marshall Posner and Eric Schadt, we functionally identify each patient’s tumor ‘drivers’. We then develop personalized fly models that are used to develop recommended drug cocktails designed to address the complexity of a patient’s tumor. Through these approaches, we are exploring the level of whole animal complexity required to usefully model human tumors,while providing candidate therapeutic approaches to the patient.
Levinson S, Cagan RL. Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell reports 2016 Sep; 16(11).
Levine BD, Cagan RL. Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic. Cell reports 2016 Jan;.
Hackett R, Moulton OC, Cagan RL. A new brand for Disease Models & Mechanisms and The Company of Biologists. Disease models & mechanisms 2015 Dec; 8(12).
Hirabayashi S, Cagan RL. Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. eLife 2015 Nov; 4.
Na J, Sweetwyne MT, Park AS, Susztak K, Cagan RL. Diet-Induced Podocyte Dysfunction in Drosophila and Mammals. Cell reports 2015 Jul;.
Hirabayashi S, Baranski TJ, Cagan RL. Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling. Cell 2013 Aug; 154(3).
Dar A, Das T, Shokat K, Cagan R. Chemical Genetic Discovery of Targets and Anti-targets for Cancer Therapy. Nature 2012; 486(7401).
Johnson R, Sedgwick A, D’Souza-Schorey C, Cagan R. Role for a Cindr-Arf6 axis in patterning emerging epithelia. Mol. Biol. Cell 2011;(22(23)): 4513-4526.
Vidal M, Salavaggione L, Ylagan L, Wilkins M, Watson M, Weilbaecher K, Cagan R. A Role for the Epithelial Microenvironment at Tumor Boundaries: Evidence from Drosophila and Human Squamous Cell Carcinomas. Am J Pathol 2010; 176(6): 3007-3014.
Cordero J, Macagno J, Stefanatos R, Strathdee K, Cagan R, Vidal M. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev Cell 2010; 15(18(6)): 999-1011.
Vidal M, Warner S, Read R, Cagan R. Differing Src signaling levels have distinct outcomes in Drosophila. Cancer Research 2007; 67(21): 10278-10285.
Vidal M, Larson D, Read R, Cagan R. Drosophila Csk regulates oncogenic growth through multiple mechanisms. Developmental Cell 2006; 10(1): 33-44.
Vidal M, Wells S, Ryan A, Cagan R. ZD6474 supresses oncogenic Ret isoforms in a Drosophila model for Type 2 Multiple > Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma . Cancer Research 2005; 65(9): 3538-3541.
Bao S, Cagan R. Preferential Adhesion mediated by Hibris and Roughest Regulates Morphogenesis and Patterning in the Drosophila Eye . Developmental Cell 2005; 8(6): 925-935.
Read R, Goodfellow P, Mardis E, Novack N, Cagan R. A Drosophila model of Multiple Endocrine Neoplasia Type 2. Genetics 2005; 171: 1057-1081.
Read R, Bach E, Cagan R. Drosophila C-terminal Src kinase negatively regulates organ growth and cell proliferation through inhibition of the Src, Jun N-terminal kinase, and STAT pathways . Mol Cell Biol 2004; 24(15): 6676-6689.
Hays R, Wickline L, Cagan R. Degradation of a Drosophila IAP by the morgue ubiquitin conjugase. Nature Cell Biology 2002; 6: 425-431.
Powell P, Wesley C, Spencer S, Cagan R. Scabrous mediates long-range signaling by Notch. Nature 2000; 409: 626-630.
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