Professor of Pediatrics
Chief, Division of Pediatric Hematology/Oncology
Vice-Chair for Research, Department of Pediatrics
Leukemogenesis, oxidative stress, calcium channels, mitochondrial bioenergetics
Hematopoiesis, bone marrow, neuroblastoma, heart, brain
HSCs, iPSCs-derived blood cells, calcium channels, mitochondria
Calcium-dependent pathways, Hif-1/2α, GSH/NADPH, Nrf2, Mitochondrial electron transport, ROS
Focus Groups: Cancer Stem Cells; Hematopoiesis;
Research Description: Basic/Translational
My laboratory has focused on studying cell proliferation and differentiation and the role of calcium in growth factor signaling. We determined that erythropoietin regulates Ca2+ influx in murine and human erythroblasts through the TRP channels TRPC2 and TRPC3, and determined the mechanisms through which Ca2+ entry through these channels is regulated. This interest in calcium in growth factor signaling and cell survival led to the study of the role of TRPM2 in oxidative stress. TRPM2 is a cation channel which gates entry of calcium and sodium in response to ADPR binding following physiological events which result in ADPR production, including oxidative stress and ischemic injury. My laboratory was the first to generate conditional TRPM2 knockout mice to study tissue-specific depletion of TRPM2 in vivo. Working with a long-time collaborator, Dr. Joseph Cheung, we used our global and tissue-specific TRPM2-KO mice to study the role of TRPM2 in oxidative damage in cardiac myocytes (AJP: Heart and Circ Physiol, 2013). We demonstrated that TRPM2 protects mouse heart from physiological ischemia and that cardiac myocytes from global and cardiac specific TRPM2 KO mice have impaired cardiac metabolism and increased ROS following ischemia-reperfusion (IR) (JBC, 2014). We are continuing to work on the role of TRPM2 in ischemic injury. My laboratory was the first to identify a short physiological isoform, TRPM2-S, which functions as a dominant negative to inhibit full-length TRPM2 (TRPM2-L) function. To examine its role in cancer, we performed studies in vitro with SH-SY5Y neuroblastoma cells and in vivo with neuroblastoma xenografts, which demonstrated that TRPM2-L also protects these cells from oxidative stress and doxorubicin, and enhances tumor survival. Inhibition of TRPM2-L dramatically reduced neuroblastoma growth and enhanced tumor responsiveness to chemotherapy through mechanisms involving modulation of HIF-1α and HIF-2α expression (JBC, 2014), decreased mitochondrial function and ATP production, and increased ROS production (JBC, 2016). We found that TRPM2 levels are high in a number of cancers including neuroblastoma, breast, melanoma, and hematopoietic malignancies including AML. Our work focuses on understanding mechanisms through which TRPM2 modulates cell survival; its role in specific malignancies including its role in leukemia; and the possibility of using TRPM2 inhibition as a novel therapeutic approach, in particular for designs that aim to kill cancer cells through increasing ROS levels or impairing mitochondrial function. Its role in stem cell viability and survival is a new are of research.
Technical expertise: Molecular biology, cell biology, animal models, calcium signaling, ROS pathways
- 1. Chen SJ, Hoffman NE, Shanmughapriya S, Bao L, Keefer K, Conrad K, Merali S, Takahashi Y, Abraham T, Hirschler-Laszkiewicz I, Wang J, Zhang X-Q, Song J, Barrero C, Shi Y, Kawasawa YI, Bayerl M, Sun T, Barbour M, Wang HG, Muniswamy M, Cheung JY, Miller BA. A Splice Variant of the Human Ion Channel TRPM2-L Modulates Neuroblastoma Tumor Growth Through HIF-1/2α. J. Biol. Chem. 289(52):36284-36302, 2014.
- 2. Hoffman NE, Miller BA, Wang J, Elrod JW, Rajan S, Gao E, Song J, Zhang X-Q, Hirschler-Laszkiewicz I Shanmughapriya S, Koch WJ, Feldman A, Muniswamy M, Cheung JY. Ca2+ entry via TRPM2 is essential for cardiac myocyte bioenergetics maintenance. American Journal of Physiology: Heart and Circulatory Physiology 308:H637-H650, 2015. (APSselect April 2015 for distinction in scholarship).
- 3. Miller BA, Cheung JYC. TRPM2 protects against tissue damage following oxidative stress and ischaemia-reperfusion. (Symposium Review). Journal of Physiology 594.15: 4181-4191, 2016.
- 4. Bao L, Chen SJ, Conrad K, Keefer K, Abraham T, Lee J, Wang J, Zhang X-Q, Hirschler-Laszkiewicz I, Wang HG, Dovat S, Gans B, Muniswamy M, Cheung JY, Miller BA. Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates its Key Role in Cell Survival through Modulation of Mitochondrial ROS and Bioenergetics. J. Biol. Chem. 291:24449-24464, 2016.