11 months ago

2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Tuberous sclerosis complex Tuberous sclerosis complex (TSC) is an autosomal-dominant multisystem disorder characterized by benign tumors in the brain, skin, heart, kidneys, and lung. These tumors cause a diverse set of clinical problems including epilepsy, learning difficulties, behavioral problems, and renal failure. TSC is caused by mutations within the TSC1 or TSC2 genes. These mutations inactivate the genes’ tumor suppressive function and drive tumor cell growth. TSC1 and TSC2 interact in a protein signaling complex in the mTOR-S6K pathway, and our lab has launched a multifaceted TSC project as part of our PI3K-mTOR and autophagy program. This research works toward new treatment options for TSC patients and will likely have broad implications for cancer patients as well. To identify novel genes and investigate their cellular dynamics, we optimized both compound and RNAi screening platforms. From our screens, we identified genes which when knocked down decreased cell viability, including genes involved in cell cycle control. We are confirming our results in additional cell lines and are exploring the outcomes in the presence of rapamycin, an effective tumor suppressor for TSC patients. Further, we are using whole-exome sequencing on TSC tissue samples and analyzing patient genomes. We have obtained 150 tissue samples from national collaborators, and samples meeting quality and yield criteria were sent for next-generation sequencing. We are collaborating with the VARI Bioinformatics core to analyze the sequencing data for meaningful genetic variants. We have opened a feasibility study at two clinical sites to pilot a personalized-medicine approach for TSC. We have used patient biopsies, genome technologies, and a team of experts to design a therapeutic protocol specific to each enrolled participant. Five patients have enrolled in the feasibility study. Our Molecular Tumor Board has reviewed patient genomic data, evaluated the molecular alterations, discussed relevant targeted therapies, and developed recommended treatment plans specific to each individual genome. Although the feasibility study does not involve patient treatment, we are working toward a clinical trial in which physicians may implement our personalized medicine approach as part of the treatment strategy. Recent Publications Goodall, Megan L., Tong Wang, Katie R. Martin, Matthew G. Kortus, Audra L. Kauffman, Jeffrey M. Trent, Steven Gately, and Jeffrey P. MacKeigan. 2014. Development of potent autophagy inhibitors that sensitize oncogenic BRAF V600E mutant melanoma tumor cells to vemurafenib. Autophagy 10(6): 1120–1136. Lanning, Nathan J., Brendan D. Looyenga, Audra L. Kauffman, Natalie M. Niemi, Jessica Sudderth, Ralph J. DeBerardinis, and Jeffrey P. MacKeigan. 2014. A mitochondrial RNAi screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of ATP levels. Cell Reports 7(3): 907–917. Niemi, Natalie M., Juliana L. Sacoman, Laura M. Westrate, L. Alex Gaither, Nathan J. Lanning, Katie R. Martin, and Jeffrey P. MacKeigan. 2014. The pseudophosphatase MK-STYX physically and genetically interacts with the mitochondrial phosphatase PTPMT1. PLoS One 9(4): e93896. Westrate, Laura M., Jeffrey A. Drocco, Katie R. Martin, William S. Hlavacek, and Jeffrey P. MacKeigan. 2014. Mitochondrial morphological features are associated with fission and fusion events. PLoS One 9(4): e95265. Westrate, Laura M., Aaron D. Sayfie, Danielle M. Burgenske, and Jeffrey P. MacKeigan. 2014. Persistent mitochondrial hyperfusion promotes G2/M accumulation and caspase-dependent cell death. PLoS One 9(3): e91911. 20

This fluorescence intensity profile shows the effects of the antimalarial agent chloroquine on sarcoma cells; the effects can be followed over time. In this image, the nucleus is stained blue, endosomes green, and lysosomes red. Chloroquine inhibits autophagy by deacidifying lysosomes so they can no longer digest cellular materials, leading eventually to cell death. Yellow peaks suggest that some lysosomes undergo autophagy even after chloroquine treatment. Image by Megan Goodall of the MacKeigan laboratory. 21

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