Browsing by Author "Senger, Donna L."

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    ATM-deficient cancer cells and targeted therapies
    (2018-07-09) Jette, Nicholas Ryan; Lees-Miller, Susan; Narendran, Aru; Senger, Donna L.; Bebb, Gwyn D.
    The driving principle behind precision medicine is to specifically target genetic variations that arise in tumorigenesis while leaving normal cells unaffected. Mutations in Ataxia Telangiectasia Mutated (ATM) may offer such a therapeutic target. ATM is mutated in a variety of tumor types and these mutations can lead to a dysfunctional protein, or protein deletion. ATM is an apex signaling kinase that responds to DNA double strand breaks, playing a direct role in DNA repair as well as the initiation of signaling cascades that can lead to cell cycle arrest and apoptosis. In recent years, several studies have shown that Poly ADP-Ribose Polymerase (PARP) inhibitors effectively target ATM-deficient tumors both invitro and invivo. These studies have been limited to mantle cell lymphoma, gastric cancer, colorectal cancer and breast cancer cell lines and the mechanism of sensitivity remains unclear. Here, I show that ATM-deficient lung and pancreatic cancer cell lines are sensitive to olaparib (a PARP inhibitor) and that ATM-deficient pancreatic cancer cell lines are sensitive to the PARP inhibitor Rucaparib as well as the ATR inhibitor VE-821. Using both lung and colorectal cancer cells, I also show that olaparib induces DNA damage and that olaparib causes an accumulation of G2 phase cells in ATM-deficient cells. Since olaparib is set to become a more commonly used chemotherapeutic, these findings are both important and relevant to its use in the clinic.
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    Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor
    (Public Library of Science, 2008-11-25) Wang, LiMei; Rahn, Jennifer J.; Lun, XueQing; Sun, Beichen; Kelly, John J. P.; Weiss, Samuel; Robbins, Stephen M.; Forsyth, Peter A.; Senger, Donna L.
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    Identification of dipeptidase-1 as an organ-selective adhesion receptor utilized by neutrophils and metastatic cancer cells in the liver and lungs
    (2018-04-30) Roy Choudhury, Saurav; Senger, Donna L.; Kubes, Paul; Liao, Shan; Morris, Don G.; Schriemer, David C.; Ferri, Lorenzo Edwin
    Lungs and liver are two major sites of neutrophil trafficking and inflammatory disease. Neutrophil recruitment in response to an inflammatory cue is a sequentially coordinated process where adhesion molecules expressed on the endothelium of a given organ mediate different steps in the classical leukocyte recruitment cascade [1]. However, molecules identified as being central in the canonical schema of neutrophil recruitment to different organs (mesentery, skin, and cremaster muscle) are not required in the inflamed pulmonary and hepatic vasculatures [2-8]. Using an unbiased functional screen in vivo, we isolated a peptide-displaying phage that homed to the liver and lungs of mice treated with a bacterial inflammatory stimulus (lipopolysaccharide). Employing intravital microscopy, we found that this phage, or its corresponding displayed-peptide, termed LSALT herein, inhibited the adhesion of neutrophils in the inflamed lungs and liver vasculatures in response to LPS. The corresponding synthetic peptide also reduced the metastatic colonization of melanoma cells to the lungs in human xenograft and immunocompetent mouse models. Using biochemical, genetic and confocal intravital imaging approaches we identified dipeptidase-1 (DPEP1) as the functional target of this peptide and established its role as a physical adhesion receptor for neutrophil and metastatic cancer cell adhesion independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment and cancer metastasis to the lungs and liver, and in models of Acute Respiratory Distress Syndrome (ARDS), prevented septic lung injury and mortality. This study identified DPEP1 as an organ-selective vascular endothelial adhesion receptor for the recruitment of neutrophils and metastatic cancer cells to the lungs and liver and identifies DPEP1 as a novel therapeutic target for systemic inflammatory disorders as well as organ-selective metastatic diseases.
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    Spatiotemporal modeling reveals high-resolution invasion states in glioblastoma
    (2024-10-10) Manoharan, Varsha T.; Abdelkareem, Aly; Gill, Gurveer; Brown, Samuel; Gillmor, Aaron; Hall, Courtney; Seo, Heewon; Narta, Kiran; Grewal, Sean; Dang, Ngoc H.; Ahn, Bo Y.; Osz, Kata; Lun, Xueqing; Mah, Laura; Zemp, Franz; Mahoney, Douglas; Senger, Donna L.; Chan, Jennifer A.; Morrissy, A. S.
    Abstract Background Diffuse invasion of glioblastoma cells through normal brain tissue is a key contributor to tumor aggressiveness, resistance to conventional therapies, and dismal prognosis in patients. A deeper understanding of how components of the tumor microenvironment (TME) contribute to overall tumor organization and to programs of invasion may reveal opportunities for improved therapeutic strategies. Results Towards this goal, we apply a novel computational workflow to a spatiotemporally profiled GBM xenograft cohort, leveraging the ability to distinguish human tumor from mouse TME to overcome previous limitations in the analysis of diffuse invasion. Our analytic approach, based on unsupervised deconvolution, performs reference-free discovery of cell types and cell activities within the complete GBM ecosystem. We present a comprehensive catalogue of 15 tumor cell programs set within the spatiotemporal context of 90 mouse brain and TME cell types, cell activities, and anatomic structures. Distinct tumor programs related to invasion align with routes of perivascular, white matter, and parenchymal invasion. Furthermore, sub-modules of genes serving as program network hubs are highly prognostic in GBM patients. Conclusion The compendium of programs presented here provides a basis for rational targeting of tumor and/or TME components. We anticipate that our approach will facilitate an ecosystem-level understanding of the immediate and long-term consequences of such perturbations, including the identification of compensatory programs that will inform improved combinatorial therapies.
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    The Transcription Factor TCF7L2 Acts in An Isoform-Specific Manner to Regulate Epithelial Cell Plasticity: Implications for Breast Cancer Cell Invasiveness and Metastasis
    (2020-06-05) Karve, Kunal; Bonni, Shirin; Riabowol, Karl T.; Senger, Donna L.; Arcellana-Panlilio, Mayi Y.; Goping, Ing Swie
    Alternative splicing of mRNA in a mammalian cell allows generation of complexity in the proteome. The consequences of splicing and its biological significance is poorly understood in development and disease conditions. The research described in thesis investigates the biological significance of alternative splicing of the pre-mRNA of the transcription factor Transcription Factor-7 Like-2 (TCF7L2) into the three major E, S and M isoforms in epithelial and carcinoma cells. Epithelial-mesenchymal transition (EMT) is a fundamental process in development and contributes to pathological conditions including cancer. EMT contributes to cellular plasticity, as it promotes epithelial cells to attain mesenchymal features. The protein TCF7L2 regulates the proliferation and differentiation of epithelial cells, however, whether TCF7L2 acts in an isoform-dependent manner to control EMT had remained largely to be elucidated. Transforming growth factor beta (TGFβ) signaling pathway is a potent inducer of EMT in normal and cancer conditions. How TGFβ-signaling-induced EMT is controlled is the subject of much investigations. The research carried out in this thesis tests the hypothesis that TCF7L2 acts in an isoform-specific manner to differentially regulate TGFβ-induced EMT in epithelial and carcinoma cells. Gain and loss of function studies were done to determine if alterations in the protein abundance of E, M, and S TCF7L2 isoforms affects EMT induction in cells grown in the context of a three-dimensional (3D) culturing system. Our data suggest that while TCF7L2E suppresses, TCF7L2M or S promotes TGFβ-induced EMT in 3D-multicellular structures derived from non-transformed epithelial cells or carcinoma cells. In other studies, we find that TGFβ signaling reduces the proportion of TCF7L2E to TCF7L2M/S protein in cells undergoing EMT. Mechanistically, we find that TCF7L2 operates via TGFβ-Smad signaling to regulate EMT. More recent studies have also identified a specific domain in the C-terminal end of TCF7LE isoforms to be required for its ability to suppress EMT. Collectively, our findings unveil novel isoform-specific functions for the transcription factor TCF7L2 and provide novel links between TCF7L2 and TGFβ signaling in the control of EMT and potentially cancer progression.