Project description:Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds to thousands of polyps that unless removed by prophylactic colectomy will progress to CRC at an early age. Non-steroidal anti-inflammatory drugs (NSAIDs) and -3 marine polyunsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA), have been evaluated for their chemopreventive potential in delaying the onset of CRC in high-risk patients. In this study, we determined whether the NSAID, naproxen, alone or in combination with a chemically-stable form of EPA (TP-252), affects tumor formation in the ApcPirc rat model. When compared to control diet, animals fed naproxen or HD TP-252 had 66%, and 82% fewer tumors respectively. However, when fed a combination of naproxen and HD TP-252, animals exhibited a 95% reduction in tumor formation and a 98% reduction in tumor volume, respectively. To elucidate potential mechanisms of tumor protection, a comprehensive, targeted lipidomic analysis was performed on colonic mucosa to determine changes in eicosanoid metabolism. Animals receiving TP-252 alone or in combination with naproxen had significantly reduced mucosal levels of pro-inflammatory -6 eicosanoids (PGE2, 5-HETE, and 14,15-DiHETrE), along with a simultaneous increase in anti-inflammatory EPA-derived -3 eicosanoids. Our colonic mucosal lipidomic analysis also uncovered several potential pharmacodynamic (PD) lipid biomarkers, including resolvin E2, 9-HEPE, 12-HEPE and 18-HEPE, that were increased in both the tissue and plasma of rats receiving TP-252 and were significantly correlated with tumor protection. Further studies with this drug combination should be focused on dose optimization and the role of EPA-derived lipid mediators in CRC initiation and progression.
Project description:Previously, we have demonstrated that the recombinant adeno-associated virus carrying the kringle domain 1 of hepatocyte growth factor (rAAV-HGFK1) gene is a potential anti-angiogenic approach for the treatment of hepatocellular carcinoma (HCC) and exerts direct inhibition effects on tumor cells. Here, using genome-wide expression profiling technology, coupled with RT-PCR validation, we investigated the differentially expressed genes and proposed the mechanisms involved in HGFK1 anti-angiogenic and anti-tumor cell signaling networks. Keywords: HGFK1, anti-angiogenic signaling network, anti-tumor cell signaling network
Project description:While angiogenesis inhibitors have provided significant clinical benefit as cancer therapeutics, the mechanisms of anti-VEGF resistance remain incompletely understood. We uncovered an interleukin-17 mediated paracrine network of signaling between the adaptive and innate immune system associated with resistance to anti-VEGF treatment in multiple tumor models. The expression of tumor-associated fibroblasts and tumor-associated granulocytes (defined as CD11b+Gr1+) and tumor-associated monocytic cells (defined as CD11b+Gr1-) were compared between wildtype and IL-17RC knockout tumor bearing mice.
Project description:Inactivation of tumor infiltrating lymphocytes (TILs) is one of the limiting factors of anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironment. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further reveals that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs during anti-tumor immunity, and that Tet2 inactivation could benefit anti-tumor immunity and suppress tumor growth.
Project description:Previously, we have demonstrated that the recombinant adeno-associated virus carrying the kringle domain 1 of hepatocyte growth factor (rAAV-HGFK1) gene is a potential anti-angiogenic approach for the treatment of hepatocellular carcinoma (HCC) and exerts direct inhibition effects on tumor cells. Here, using genome-wide expression profiling technology, coupled with RT-PCR validation, we investigated the differentially expressed genes and proposed the mechanisms involved in HGFK1 anti-angiogenic and anti-tumor cell signaling networks. Keywords: HGFK1, anti-angiogenic signaling network, anti-tumor cell signaling network Microarray probe sets which were at least 2-fold changed upon rAAV-HGFK1 treatment when compared to rAAV-EGFP (baseline control) treatment on the cells are considered as differentially expressed genes (DEGs). The differentially expressed genes were analyzed using two software tools, namely PathwayArchitect (version 1.0.0) (www.strategene.com) and Ingenity Pathways Analysis (version 5.0) (http://www.ingenuity.com/index.html). They are designed to assist microarray data analysis and provide visualization of biological pathways, gene regulation networks and protein-protein interactions to users. The signaling networks proposed above were manually determined and created based on the relevant findings in literature provided by the software tools.
Project description:While angiogenesis inhibitors have provided significant clinical benefit as cancer therapeutics, the mechanisms of anti-VEGF resistance remain incompletely understood. We uncovered an interleukin-17 mediated paracrine network of signaling between the adaptive and innate immune system associated with resistance to anti-VEGF treatment in multiple tumor models.
Project description:BCL-2 family proteins control cell fate by regulating the mitochondrial apoptotic pathway. Anti-apoptotic members suppress cell death by capturing pro-apoptotic α-helices in a surface groove, a mechanism hijacked by cancer cells to enforce cellular immortality. We previously identified and harnessed a unique cysteine (C55) in the canonical groove of anti-apoptotic BFL-1 to selectively neutralize its oncogenic activity using a covalent stapled-peptide inhibitor. Here, we find that disulfide bonding between a native cysteine pair at the interface between the groove (C55) and C-terminal α9 helix (C175) operates as a redox switch to control the accessibility and functionality of the anti-apoptotic pocket. Hydrogen deuterium exchange mass spectrometry was used to characterize a construct of BFL-1 deleting the C-terminus and thus C175 (BFL-1ΔC C55), as well as full length BFL-1 (BFL-1 C55/C175) in both oxidation states. Reducing the C55-C175 disulfide bond triggers a cascade of structure-function changes that includes release of α9 for membrane translocation, exposure of the groove for α-helical interaction, and resultant blockade of mitochondrial membrane permeabilization by pro-apoptotic BAX. Thus, we identify a unique mechanism of conformational control over anti-apoptotic activity by a redox switch in BFL-1.
Project description:Small, soluble metabolites are not only essential intermediates in intracellular biochemical processes, but can also influence neighboring cells when released into the extracellular milieu. Here, we identify the metabolite and neurotransmitter GABA as a candidate signaling molecule synthesized and secreted by activated B cells and plasma cells. We show that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages which secrete IL-10 and inhibit CD8+ T cell killer function. In mice, B cell deficiency or B cell-specific inactivation of the GABA generating enzyme GAD67 enhances anti-tumor responses. Our study reveals that in addition to cytokines and membrane proteins, small metabolites derived from B lineage cells have immunoregulatory functions, which may be pharmaceutical targets allowing fine-tuning of immune responses.