EDINGER LAB
Dissecting the signals that control endolysosomal trafficking in health and disease.SPHINGOLIPIDS
Modulate metabolism, growth, and survival from yeast to mammals in part by limiting endocytic recycling and lysosomal trafficking.
MACROPINOCYTOSIS
Is a mechanism for nutrient acquisition and drug resistance in cancer cells.
DRUG DEVELOPMENT
Synthetic sphingolipids and macropinocytosis inhibitors could offer significant therapeutic benefits in cancer, obesity, and other diseases.
Welcome to the Edinger Lab
We use interdisciplinary, collaborative approaches to dissect how intracellular trafficking pathways could be modulated to treat lethal human diseases like cancer and obesity. One focus of the lab is the backbone of all sphingolipids: sphingosine. Sphingosine in mammals and phytosphingosine in yeast are endogenous molecules that have been optimized by evolution to promote homeostatic growth. By activating protein phosphatase 2A, these sphingolipids have pleiotropic effects on intracellular trafficking that are distinct from those of the toxic sphingolipid ceramide. We have developed synthetic sphingosine analogs as tool compounds to dissect the unique functions of this class of sphingolipids. These compounds have good drug-like properties and striking effects in vivo. For example, our synthetic sphingolipids limit prostate tumor growth. Moreover, their effects on endolyososomal trafficking limit mitochondrial fission in vitro and in vivo, protecting cells from the ER stress and enhanced ROS generation that trigger metabolic dysfunction during obesity. We have also uncovered a role for macropinocytosis in tumor drug resistance. Necrotic cell debris present in almost every tumor is a rich nutrient source that eliminates cancer cell dependence on the biosynthetic pathways targeted by many standard of care cancer therapeutics. By understanding the signals that drive macropinocytosis, we hope to identify drugs that can overcome resistance to these therapies. Finally, we hope to exploit our ability to control endolysosomal trafficking pathways to enhance the delivery of nucleotide therapeutics that enter target cells via endocytosis or macropinocytosis.
Goal
Dissect the signals regulating endocytic trafficking and use this knowledge to treat lethal human diseases such as cancer and obesity.
Unmet Need
Drug resistance limits our ability to treat cancer. Obesity therapeutics have historical problems with low efficacy and unacceptable toxicity. The use of nucleotide therapeutics is limited by our ability to efficiently deliver these drugs to their intracellular targets.
Innovation
Drugs targeting endocytic trafficking are not widely used clinically. Using natural sphingolipids as the template for therapeutics allows us to capture their pleiotropic effects that have been optimized by evolution for robustness and low toxicity.
Aimee Edinger, VMD/PhD
Aimee Edinger is a Professor of Developmental and Cell Biology and Chancellor’s Fellow in the UC Irvine School of Biological Sciences, a member of the NCI-designated Chao Family Comprehensive Cancer Center at UCI, and a AAAS Fellow. She joined UCI in 2005 after completing a PhD in Virology, veterinary training (VMD), and a postdoctoral fellowship in Cancer Metabolism at the University of Pennsylvania in Philadelphia. Professor Edinger is the Associate Director of the UCI Cancer Research Institute and co-Director of the NCI T32 Training Grant that supports interdisciplinary cancer research training at UCI. Edinger lab research in leukemia, prostate, and breast cancer models has been funded by the National Cancer Institute, the National Institute of General Medical Sciences, the American Cancer Society, the Department of Defense’s Congressionally Directed Medical Research Program, the University of California Cancer Research Coordinating Committee, the Gabrielle’s Angel Foundation, the Ono Pharma Foundation, the William Lawrence and Blanche Hughes Foundation, the UCI Chao Family Comprehensive Cancer Center, the Anti-Cancer Challenge, and UCI Applied Innovation. Dr. Edinger is an inventor on seven patents with others in process.
Professor Edinger has taught several of UCI’s undergraduate and graduate core courses and is actively engaged in the development of an Honors curriculum focused on critical analysis of primary research data and intellectual risk-taking. The Edinger lab includes a cohort of dedicated undergraduate researchers who make key contributions to our discovery efforts and publications. Dr. Edinger’s efforts to support UCI’s teaching mission have been recognized by the 2021 De Gallow UCI Professor of the Year award, a Chancellor’s Award for Excellence in Undergraduate Research, and a Golden Apple teaching award from the School of Biological Sciences. Dr. Edinger has served as the Equity Advisor for the School since 2016. In this role, she works with School leadership to promote diversity, equity, and inclusion.
Current research in the Edinger Lab focuses on:
SPHINGOLIPIDS AND GROWTH CONTROL
Sphingolipids have been called “tumor suppressor lipids” because they slow cell growth, induce differentiation, and trigger programmed cell death. Sphingolipids were named after the Sphinx due to their enigmatic actions. We dissect the complex molecular mechanisms underlying the ability of sphingolipids to restrict cancer initiation and growth with a focus on how these lipids control the endocytosis of cell-surface nutrient transporter proteins and the decision point where these proteins are either recycled back to the plasma membrane or sent to the lysosome for degradation. This work has revealed evolutionarily-conserved mechanisms for growth control that are disrupted in cancer cells.
DRUG DEVELOPMENT AND CHEMICAL BIOLOGY
In collaboration with chemist Stephen Hanessian, PhD, we have developed novel synthetic sphingolipids with good pharmaceutical properties. Like the natural sphingolipids that they are templated on, our compounds modulate intracellular trafficking. Unlike endogenous sphingolipids, our drug-like versions are resistant to metabolism into other sphingolipid forms with opposing, negative effects. We have demonstrated that these water-soluble, orally bioavailable molecules are safe and effective in models of cancer and obesity. This work has led to the launch of a start-up biotech company that is moving these molecules towards clinical trials. These synthetic sphingolipids are also being used to dissect the protein targets responsible for the multifaceted effects of sphingosine analogs.
MACROPINOCYTOSIS AND NUTRIENT SCAVENGING
Nutrient delivery to tumor cells is limited by abnormal, leaky blood vessels. When glucose, amino acids, and other building blocks are limited, cancer cells scavenge macromolecules from the tumor microenvironment and then degrade them into subunits that are used to fuel growth. Macropinocytosis is a non-specific, bulk uptake process through which macromolecules and small debris can be engulfed by membrane ruffles that close into large (0.2 – 5 μm) macropinosomes. Our work has shown that prostate and breast cancers rely on macropinocytosis to support their growth and survival. Inhibitors of macropinocytosis limit tumor growth in mice. Moveover, macropinocytosis confers resistance to chemotherapeutics like 5-FU and gemcitabine that target biosynthetic pathways. We are dissecting the molecular signals that control macropinocytosis with the goal of developing safe and effective inhibitors that can be used therapeutically.
ANTI-SENSE OLIGONUCLEOTIDE POTENTIATION
Antisense oligonucleotides (ASO) can, in principle, trigger the degradation of any cellular RNA. While many barriers to the widespread clinical use of ASO have been overcome by medicinal chemistry advances over the last three decades, the application of this powerful platform technology is limited by the inefficient entry of ASO into the cytosol of target cells. Our efforts to understand the signals that control endolysosomal trafficking have suggested several new ways to increase ASO uptake and release. Small molecules that potentiate ASO activity would have widespread clinical applications in patients with many diseases.