Welcome to Our Lab
Dr. Miller’s lab is part of the Department of Pediatrics, Division of Hematology/Oncology, at Penn State College of Medicine in Hershey, Pennsylvania. The lab is funded by the National Institutes for Health, Four Diamonds, and Hyundai Hope on Wheels.
Our Research
Research in this laboratory is currently focused on studying an ion channel called TRPM2. This channel is found in many cell types and has an important role in proliferation and survival. Dr. Miller’s lab recently demonstrated that TRPM2 channels are highly expressed in neuroblastoma, the most common pediatric solid tumor outside the brain, as well as in other cancers including melanoma, lung, breast cancer and leukemia. Using mouse models, Dr. Miller’s lab found that neuroblastomas expressing full length TRPM2-L channels grow much larger than tumors in which TRPM2 is inhibited, making this a novel target for anti-cancer therapies.
Research Highlights
TRPM in Cancer
Miller, B.
The TRP ion channel TRPM2 has an essential function in cell survival and protects the viability of a number of cell types after oxidative stress. It is highly expressed in many cancers including breast, prostate, and pancreatic cancer, melanoma, leukemia, and neuroblastoma, suggesting it promotes cancer cell survival. In a number of cancers including neuroblastoma, TRPM2 has been shown to preserve viability and mechanisms have been identified. Evidence suggests that targeting TRPM2 may be a novel therapeutic approach in many cancers.
Depletion of the human ion channel TRPM2 in neuroblastoma demonstrates its key role in cell survival through modulation of mitochondrial reactive oxygen species and bioenergetics
Lei Bao, et al.
Transient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in modulating cell survival following oxidant injury and is highly expressed in many cancers, including neuroblastoma. In xenografts generated from neuroblastoma cells in which TRPM2 was depleted with CRISPR/Cas9 technology and in in vitro experiments, tumor growth was significantly inhibited and doxorubicin sensitivity increased. Our findings demonstrate the important function of TRPM2 in modulation of cell survival through mitochondrial ROS, and the potential of targeted inhibition of TRPM2 as a therapeutic approach to reduce cellular bioenergetics, tumor growth, and enhance susceptibility to chemotherapeutic agents.
A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α
Shu Jen Chen, et al.
Calcium-permeable ion channel TRPM2 is highly expressed in a number of cancers. In this study we used xenografts generated with SH-SY5Y neuroblastoma cells stably expressing TRPM2 isoforms to show that growth of tumors expressing TRPM2-S was significantly reduced compared with tumors expressing TRPM2-L. Inhibition of TRPM2-L by pretreatment with clotrimazole or expression of TRPM2-S significantly increased sensitivity of cells to doxorubicin. Our study suggests that TRPM2 activity is important for tumor growth and for cell viability and survival following doxorubicin treatment, and that interference with TRPM2-L function may be a novel approach to reduce tumor growth through modulation of HIF-1/2α, mitochondrial function, and mitophagy.
Role of TRPM2 in cell proliferation and susceptibility to oxidative stress
Shu Jen Chen, et al.
The transient receptor potential (TRP) channel TRPM2 is an ion channel that modulates cell survival. To differentiate the roles of TRPM2-L and TRPM2-S (both expressed at significantly higher rates in human neuroblastoma compared with adrenal gland), we established neuroblastoma SH-SY5Y cell lines stably expressing either TRPM2 isoform or empty vector. Cells expressing TRPM2-S showed significantly enhanced proliferation, downregulation of phosphatase and tensin homolog (PTEN), and increased protein kinase B (Akt) phosphorylation and cell surface glucose transporter 1 (Glut1) compared with cells expressing TRPM2-L or empty vector. On the other hand, TRPM2-S-expressing cells were significantly more susceptible to cell death induced by low H2O2 concentrations, wherease TRPM2-L-expressing cells were protected.
The Human Ion Channel TRPM2 Modulates Neuroblastoma Cell Survival and Mitochondrial Function through Pyk2, CREB, and MCU activation
Iwona Hirschler-Laszkiewicz, et al.
The transient receptor potential (TRP) channel TRPM2 has an essential function in cell survival and is highly expressed in many cancers. Inhibition in neuroblastoma has been shown to significantly reduce cell viability. Here, the role of proline-rich tyrosine kinase 2 (Pyk2) in TRPM2 modulation of neuroblastoma viability was explored. In TRPM2-depleted cells, phosphorylation and expression of Pyk2 and cAMP-responsive element-binding protein (CREB), a downstream target, were significantly reduced after application of doxorubicin. Our results demonstrated that TRPM2 expression protects the viability of neuroblastoma through Src, Pyk2, CREB, and MCU activation, all of which play key roles in maintaining mitochondrial function and cellular bioenergetics.