👤 Lillian R Klug

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates. Show less

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases. Show less

Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by a steatosis of the liver that may progress to more serious pathological conditions including: nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As the prevalence of NAFLD has increased worldwide in recent years, pathophysiology and risk factors associated with disease progression of NAFLD are at the focus of many studies. NAFLD is related to and shares common serum biomarkers with cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). West Virginia (WV) is a state with some of the highest rates of CVD, obesity and diabetes mellitus. As NAFLD is closely related to these diseases, it is of particular interest in WV. Currently there is no cost-effective, standardized method used clinically to detect NAFLD prior to the onset of reversible complications. At this time, the diagnosis of NAFLD is made with costly radiologic studies and invasive biopsy. These studies are only diagnostic once changes to hepatic tissue have occurred. The diagnosis of NAFLD by traditional methods may not allow for successful intervention and may not be readily available in areas with already sparse medical resources. In this literature review, we identify a list of biomarkers common among CVD, T2DM, obesity, MetS and NAFLD. From this research we propose the following biomarkers are good candidates for inclusion in a panel of biomarkers for the early detection of NAFLD: adiponectin, AST, ALT, apo-B, CK18, CPS1, CRP, FABP-1, ferritin, GGT, GRP78, HDL-C, IGF-1, IL-1β, 6, 8, 10, IRS-2PAI-1, leptin, lumican, MDA SREBP-1c and TNF-α. Creating and implementing a biomarker panel for the early detection and attenuation of NAFLD, prior to the onset of irreversible complication would provide maximum benefit and decrease the disease burden on the patients and healthcare system of WV. Show less