Approximately 10-20% of thyroid cancers are driven by gene fusions, which activate oncogenic signaling through aberrant overexpression, ligand-independent dimerization or loss of inhibitory motifs. We Show more
Approximately 10-20% of thyroid cancers are driven by gene fusions, which activate oncogenic signaling through aberrant overexpression, ligand-independent dimerization or loss of inhibitory motifs. We identified 13 thyroid tumors with thyroglobulin (TG) gene fusions and aimed to assess their histopathology and the fusions' oncogenic and tumorigenic properties. Of eleven cases with surgical pathology, 82% were carcinomas and 18% were noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). TG fusions preserved exon(s) 1, 1-15, 1-35 or most frequently, 1-47 of TG and, based on the 3' partner were grouped as i) involving receptor tyrosine kinases (RTKs) (TG::FGFR1, TG::RET, TG::ALK and TG::NTRK1), ii) driving aberrant DPRX and chromosome 19 microRNA cluster expression (TG::DPRX) or iii) involving IGF2 mRNA-binding protein (TG::IGF2BP1). All 13 fusion-positive tumors exhibited strong (8.5 ± 3.3 log2-fold) 3' partner overexpression driven by the TG promoter. Gene expression analysis revealed TG::RET- and TG::ALK-positive tumors being BRAFV600E-like and remaining tumors RAS-like. In thyroid PCCL3 cells, the TG::NTRK1 fusion demonstrated both spontaneous and ligand-associated dimerization, activated downstream MAPK, AKT and STAT3 signaling and drove xenograft tumorigenesis in nude mice. FDA-approved NTRK inhibitors entrectinib and larotrectinib effectively blocked TG::NTRK1 signaling in vitro and inhibited xenograft tumor growth in vivo. In summary, we report a spectrum of TG gene fusions as recurrent oncogenic events in thyroid cancer and NIFTP that drive strong overexpression of partner genes, frequently RTKs. The TG::NTRK1 fusion is prone to dimerization, activates oncogenic signaling, drives tumorigenesis in thyroid cells and, like other fusions involving RTKs, represents a potential therapeutic target in thyroid cancer. Show less
High density lipoproteins (HDL) are key components of reverse cholesterol transport pathway. HDL removes excessive cholesterol from peripheral cells, including macrophages, providing protection from c Show more
High density lipoproteins (HDL) are key components of reverse cholesterol transport pathway. HDL removes excessive cholesterol from peripheral cells, including macrophages, providing protection from cholesterol accumulation and conversion into foam cells, which is a key event in pathogenesis of atherosclerosis. The mechanism of cellular cholesterol efflux stimulation by HDL involves interaction with the ABCA1 lipid transporter and ensuing transfer of cholesterol to HDL particles. In this study, we looked for additional proteins contributing to HDL-dependent cholesterol efflux. Using RNAseq, we analyzed mRNAs induced by HDL in human monocyte-derived macrophages and identified three genes, fatty acid desaturase 1 (FADS1), insulin induced gene 1 (INSIG1), and the low-density lipoprotein receptor (LDLR), expression of which was significantly upregulated by HDL. We individually knocked down these genes in THP-1 cells using gene silencing by siRNA, and measured cellular cholesterol efflux to HDL. Knock down of FADS1 did not significantly change cholesterol efflux (p = 0.70), but knockdown of INSIG1 and LDLR resulted in highly significant reduction of the efflux to HDL (67% and 75% of control, respectively, p < 0.001). Importantly, the suppression of cholesterol efflux was independent of known effects of these genes on cellular cholesterol content, as cells were loaded with cholesterol using acetylated LDL. These results indicate that HDL particles stimulate expression of genes that enhance cellular cholesterol transfer to HDL. Show less