Browsing by Author "Senger, Donna"

Now showing 1 - 6 of 6
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    The Impact of the Innate Immune System in Alveolar Soft Part Sarcoma
    (2022-11-15) Philippot, Alexis Marie; Senger, Donna; Chan, Jennifer; Monument, Michael; Narendran, Aru
    Alveolar Soft Part Sarcoma (ASPS) is a rare pediatric malignancy which has characteristically poor clinical outcomes, largely due to a complete lack of chemotherapeutic treatment options, and a high likelihood of metastasis. Further, a lack of pre-clinical models has hampered progression in the understanding of the tumor’s biology and resistance to chemotherapies since it was originally described in 1952. After being in the privileged position of receiving ASPS tumor tissue from the lung metastasis of a 14-year-old female, the Senger laboratory successfully established an ASPS patient derived xenograft (PDX) model and corresponding cell line. Recent literature has suggested that the tumor microenvironment (TME) is implicated in the tumor progression of multiple soft tissue sarcomas, including ASPS; specifically, macrophage have been described as a prominent prognostic marker. Therefore, using this PDX model, we characterized the innate immune component of the TME with respect to the cell populations and cytokines secreted by both the tumor cells and stroma. Unsurprisingly, the PDX tumors were abundant in pro-tumor macrophage and pro-inflammatory cytokines. As data generated by the Senger laboratory had established the susceptibility of ASPS cells to proteasome inhibitor carfilzomib, carfilzomib was also evaluated for its anti-tumor implications on both the tumor cells and the innate immune microenvironment. After observing a number of anti-tumor changes to the macrophage within the TME following carfilzomib treatment, this chemotherapeutic significantly decreased tumor burden in ASPS PDX bearing mice suggesting the TME may be the Achille’s heel to this chemotherapy resistant sarcoma.
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    Innate immune signaling is modulated by the kaposin locus from Kaposi's sarcoma-associated herpesvirus
    (2024-08-06) Katsademas, Thalia Agnes; Corcoran, Jennifer A.; Senger, Donna; Shutt, Timothy
    Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of the endothelial cell (EC) cancer Kaposi’s Sarcoma (KS). Pathogenesis is dependent on effective infection, establishment and maintenance of viral latency, and periodic lytic virus reactivation. All phases of this replicative cycle rely on effective modulation of host cell immune signaling. The viral gene kaposin and its’ associated protein, KapB, are expressed in all phases of infection. However, the roles of the kaposin transcript and KapB in immune signaling remains uninvestigated. My research uncovered a novel role for KapB in blocking activation of innate immune signaling. Innate immune signaling can be controlled through a variety of regulatory molecules including proteins and RNA. I found that the kaposin RNA was responsible for blocking innate immune promoter activation. Additionally, I demonstrated that both the RNA and protein products contribute to other known KapB phenotypes of stabilization of an AU-rich element-mRNA reporter and processing body disassembly. Collectively, these data suggest that KapB utilizes both the kaposin RNA and KapB protein products to fine-tune inflammatory signaling, contributing to a permissive microenvironment for viral infection.
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    Molecular Mechanisms and Functional Role of Hepatic Invariant Natural Killer T cell Recruitment Following Sterile Injury in the Liver
    (2017) Liew, Pei; Kubes, Paul; Mody, Christopher; Eksteen, Bertus; Mallevaey, Thierry; Senger, Donna
    After traumatic injury, the body must return to homeostasis as quickly as possible through initial destruction of injured cells and clearance of debris (inflammation) followed by a critical switch towards vascular and tissue reconstruction (non-inflammatory restitution). While many different immune cells are known to infiltrate a site of injury for specific effector functions, it is reasonable to hypothesize that some cells function as directors of inflammation whereupon sensing the degree of injury, these cells orchestrate the local immune response towards a restitution phase by affecting the local cytokine milieu. This progression could be defective in non-resolving sterile injuries where a failure to transition to repair or a persistence of inflammation leads to chronic inflammation. Invariant Natural Killer T (iNKT) cells are innate lymphocytes that prominently regulate inflammation due to their rapid release of pivotal cytokines during pathological states, which can then differentially impact the downstream immune response and disease outcome. In this thesis, using intravital microscopy, we observed that patrolling iNKT cells in the liver were initially selectively repelled from a site of hepatic injury but were subsequently strategically arrested via self-antigens and cytokines, circumscribing the injured site at exactly the location where monocytes co-localized and hepatocytes proliferated. iNKT cell activation signals were temporally- and spatially-regulated as self-antigen presentation via CD1d occurred first before being closely followed by cytokine signaling. Additionally, both activation signals were located adjacent to the injury and not further away. Activation of iNKT cells through these two mechanisms resulted in the production of IL-4 but not IFN-γ which promoted increased hepatocyte proliferation, monocyte transition (from classical to tissue repair monocytes) and improved healing. Disruption of any of these mechanisms led to a delay of wound healing. We show that self-antigens, beyond the known role in iNKT cell development, were fundamental for monocyte transition, appropriate collagen deposition and hepatocyte proliferation. Hepatic iNKT cells were instrumental in directing and modulating the transformation from inflammation to tissue restitution after sterile injury in the liver for essential timely wound repair.
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    QuantitativeT2: interactive quantitative T2 MRI witnessed in mouse glioblastoma
    (Scientific Research Publishing, 2015-07-21) Ali, Tonima; Bjarnason, Thorarin; Senger, Donna; Dunn, Jeff F.; Joseph, Jeffery; Mitchell, Joseph
    The aim of this study was to establish an advanced analytical platform for complex in vivo pathologies. We have developed a software program, QuantitativeT2, for voxel-based real-time quantitative T2 magnetic resonance imaging. We analyzed murine brain tumors to confirm feasibility of our method for neurological conditions. Anesthetized mice (with invasive gliomas, and controls) were imaged on a 9.4 Tesla scanner using a Carr–Purcell–Meiboom–Gill sequence. The multiecho T2 decays from axial brain slices were analyzed using QuantitativeT2. T2 distribution histograms demonstrated substantial characteristic differences between normal and pathological brain tissues. Voxel-based quantitative maps of tissue water fraction (WF) and geometric mean T2 (gmT2) revealed the heterogeneous alterations to water compartmentalization caused by pathology. The numeric distribution of WF and gmT2 indicated the extent of tumor infiltration. Relative evaluations between in vivo scans and ex vivo histology indicated that the T2s between 30 and 150 ms were related to cellular density and the integrity of the extracellular matrix. Overall, QuantitativeT2 has demonstrated significant advancements in qT2 analysis with real-time operation. It is interactive with an intuitive workflow; can analyze data from many MR manufacturers; and is released as open-source code to encourage examination, improvement, and expansion of this method.
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    Use of Novel Anti-inflammatory Agents to Inhibit Osteosarcoma Lung Metastasis
    (2016) Wierenga, Lauren; Senger, Donna; Beaudry, Paul; McCafferty, Donna-Marie
    Currently the 5-year survival rate for osteosarcoma patients with pulmonary metastasis is less than 30%, identifying a need for novel approaches to inhibit metastasis. Consistent with an emerging understanding of the cancer-inflammation relationship, a requirement for neutrophils in metastasis was recently proposed. Here we assessed the potential requisite of neutrophils and the effects of two novel anti-inflammatory agents in osteosarcoma metastasis: LT-peptide and GML (GM1-Targeted Linoleate-Containing TLR2 Ligand). Using an osteosarcoma lung metastatic mouse model, we found increased neutrophil levels in the lungs in the presence of osteosarcoma cells and reduced metastatic burden following antibody-mediated neutrophil depletion or GML treatment. These preclinical studies identify targeting neutrophils as a novel therapeutic paradigm in osteosarcoma metastasis and contribute to our understanding of the mechanisms involved in metastatic osteosarcoma, thus supporting the development of anti-inflammatory therapies as a promising approach to improve the outcomes of osteosarcoma patients.