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Browsing by Author "Barwick, Benjamin G."
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Item PDZ proteins SCRIB and DLG1 regulate myeloma cell surface CD86 expression, growth, and survival(American Association for Cancer Research, 2022) Moser-Katz, Tyler; Gavile, Catherine M.; Barwick, Benjamin G.; Lee, Kelvin P.; Boise, Lawrence H.; Medicine, School of MedicineDespite advances in the treatment of multiple myeloma in the past decades, the disease remains incurable, and understanding signals and molecules that can control myeloma growth and survival are important for the development of novel therapeutic strategies. One such molecule, CD86, regulates multiple myeloma cell survival via its interaction with CD28 and signaling through its cytoplasmic tail. Although the CD86 cytoplasmic tail has been shown to be involved in drug resistance and can induce molecular changes in multiple myeloma cells, its function has been largely unexplored. Here, we show that CD86 cytoplasmic tail has a role in trafficking CD86 to the cell surface. This is due in part to a PDZ-binding motif at its C-terminus which is important for proper trafficking from the Golgi apparatus. BioID analysis revealed 10 PDZ domain-containing proteins proximal to CD86 cytoplasmic tail in myeloma cells. Among them, we found the planar cell polarity proteins, SCRIB and DLG1, are important for proper CD86 surface expression and the growth and survival of myeloma cells. These findings indicate a mechanism by which myeloma cells confer cellular survival and drug resistance and indicate a possible motif to target for therapeutic gain.Item Ten-eleven translocation protein 1 modulates medulloblastoma progression(BMC, 2021-04-29) Kim, Hyerim; Kang, Yunhee; Li, Yujing; Chen, Li; Lin, Li; Johnson, Nicholas D.; Zhu, Dan; Robinson, M. Hope; McSwain, Leon; Barwick, Benjamin G.; Yuan, Xianrui; Liao, Xinbin; Zhao, Jie; Zhang, Zhiping; Shu, Qiang; Chen, Jianjun; Allen, Emily G.; Kenney, Anna M.; Castellino, Robert C.; Van Meir, Erwin G.; Conneely, Karen N.; Vertino, Paula M.; Jin, Peng; Li, Jian; Biostatistics, School of Public HealthBackground: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes. Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes. Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.Item Wnt signaling in triple negative breast cancer is associated with metastasis(BioMed Central, 2013-11) Dey, Nandini; Barwick, Benjamin G.; Moreno, Carlos S.; Ordanic-Kodani, Maja; Chen, Zhengjia; Oprea-Ilies, Gabriella; Tang, Weining; Catzavelos, Charles; Kerstann, Kimberly F.; Sledge, George W., Jr; Abramovitz, Mark; Bouzyk, Mark; De, Pradip; Leyland-Jones, Brian R.; Department of Medicine, IU School of MedicineBackground Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies. Methods We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease. Results The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases. Conclusion These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.