Michael Stacey
Research Associate Professor
PHONE: 757 683 2245
EMAIL: mstacey@odu.edu
ADDRESS: IRP 2, 4211 Monarch Way, Norfolk, VA, 23508
Education
- Postdoctoral Research fellow: Followship in Cancer Pharmacology, University of Oxford, England. 1994-97
- Postdoctoral Research fellow: Fellowship in Clinical Genetics, University of Birmingham, England. 1991-94
- Ph.D.: Cancer predisposing syndromes in the Institute of Cancer and Genomic Sciences, University of Birmingham. 1995
- B.S.: Zoology. University of Hull, England. 1981
Caleb Wyckoff, Ph.D. student
Research Description
Cancers with mutations in IDH1 and IDH2 genes are complex and may have differential carcinogenic potential dependent upon which IDH gene is mutated. Chondrosarcoma and glioblastoma are two examples of cancers harboring these mutations. Interestingly, patients with glioblastoma showing mutant IDH1 have lower levels of expression of the nuclear membrane protein LMNB1 (Lamin-B1) compared to wild type patients who have increased expression, with higher grade tumors showing highest levels. Nuclear lamins play important roles in the anchorage of peripheral elements of chromatin, in regulating the organization of chromosome territories, and in gene expression. Chondrosarcomas have either IDH1, or IDH2 mutant genes, rarely both. This allows us to investigate IDH2mut/IDH1wt cells for expression of LMNB1 and to determine whether different carcinogenic pathways are active in IDH1 vs IDH2 mutant chondrosarcoma cells.
Chondrosarcomas (CS) are the second most common form of bone cancer with high malignant potential and resistance to chemo and radiation therapies. Treatments have not advanced in the last three decades and overall survivability is reduced close to zero in patients with inoperable and late-stage CS tumors, highlighting a critical need for treatment options targeting early events. We are investigating critical pathways directly applicable to CS and importantly, to other tumors harboring similar defects including, 1); the consequences of acquiring IDH1 or IDH2 mutations, 2); levels of differential LMNB1 expression in IDH1/IDH2 mutant CS and the impact of LMNB1 expression on nuclear stability, 3); mechanisms of nanosecond pulsed electric field exposure on nuclear membrane disruption, 4); changes in gene expression as a result of hierarchical rearrangement of DNA due to differential expression of LMNB1 and 5); therapeutic measures. While IDH1/ IDH2 mutations and LMNB1 expression are considered significant events in the carcinogenic process, preclinical/clinical options enabling multi-targeting of the biology associated with these mutations are lacking. Mutant IDH1 and IDH2 processes occur in the cytosol and in the mitochondria, respectively, where the availability of the D2HG generated oncometabolite to other cells is dependent on the mode of transport from one cell to another. D2HG produced in the cytosol by IDH1 is readily available for transfer either as cargo in vesicles or direct secretion into the extracellular milieu, whereas D2HG produced in the mitochondria by IDH2 is available to other cells through mitochondria transfer. D2HG can accumulate in parent and recipient cells affecting cellular physiology and increasing oncogenicity by: 1) Induction of aerobic glycolysis by preventing the breakdown of hypoxia-inducible factor 1-alpha (HIF1-a), generating a switch from aerobic oxidative metabolism to aerobic-glycolytic metabolism; 2) Induction of DNA hypermethylation resulting in dysregulated gene expression; and 3) Reduction of immune responses through decreased activation of natural killer T-cells (NK), T-helper cells (CD4), and differentiation of dendritic cells (DCs).
The over-expression of the nuclear membrane protein lamin-B1 has been shown in other cancers to induce increased proliferation, however its role in the carcinogenic processes in chondrosarcomas are unknown. We have shown in other cancer types that lamin-B1 is expressed and that some cancer types show rupture of the nuclear membrane following exposure to nsPEF, whereas others do not (Fig 2). We will determine any correlation of LMNB1 expression with sensitivity to nsPEF and determine additional epigenetic changes because of nsPEF exposure.
A) Phase contrast image of two chondrocytes joined by a membrane nanotube bridge (white arrow). B) Mitochondria (green) apparently shared between two SW1353 cells (arrowed).
Cells stained for Lamin-B1 showing normal nuclei and ruptured nuclei following exposure to nsPEF. Taken from Stacey M, et al (2011) Nanosecond pulsed electric field induced cytoskeleton, nuclear membrane and telomere damage adversely impact cell survival. Bioelectrochemistry. 82 131-134