It is now well accepted that cancer cells change their microenvironment from normal to tumor-supportive state to provide sustained tumor growth, metastasis and drug resistance. These processes are partially carried out by exosomes, nano-sized vesicles secreted from cells, shuttled from donor to recipient cells containing a cargo of nucleic acids, proteins and lipids. By transferring biologically active molecules, cancer-derived exosomes may transform microenvironmental cells to become tumor supportive. Telomerase activity is regarded as a hallmark of cancer. We have recently shown that the transcript of human telomerase reverse transcriptase (hTERT), is packaged in cancer cells derived- exosomes. Following the engulfment of the hTERT transcript into fibroblasts, it is translated into a fully active enzyme [after assembly with its RNA component (hTERC) subunit]. Telomerase activity in the recipient, otherwise telomerase negative cells, provides them with a survival advantage. Here we show that exosomal telomerase might play a role in modifying normal fibroblasts into cancer associated fibroblasts (CAFs) by upregulating $$\mathrm{\alpha }$$ α SMA and Vimentin, two CAF markers. We also show that telomerase activity changes the transcriptome of microRNA in these fibroblasts. By ectopically expressing microRNA 342, one of the top identified microRNAs, we show that it may mediate the proliferative phenotype that these cells acquire upon taking-up exosomal hTERT, providing them with a survival advantage.
Large scale cancer genomics data provide crucial information about the disease and reveal points of intervention. However, systematic data have been collected in specific cell lines and their collection is laborious and costly. Hence, there is a need to develop computational models that can predict such data for any genomic context of interest. Here we develop novel models that build on variational graph auto-encoders and can integrate diverse types of data to provide high quality predictions of genetic interactions, cell line dependencies and drug sensitivities, outperforming previous methods. Our models, data and implementation are available at: https://github.com/aijag/drugGraphNet.
It is now well accepted that cancer cells change their microenvironment from normal to tumor-supportive state to provide sustained tumor growth, metastasis and drug resistance. These processes are partially carried out by exosomes, nano-sized vesicles secreted from cells, shuttled from donor to recipient cells containing a cargo of nucleic acids, proteins and lipids. By transferring biologically active molecules, cancer-derived exosomes may educate microenvironmental cells to become tumor supportive. We have recently shown that the transcript of human telomerase reverse transcriptase (hTERT), the hallmark of cancer cells is packaged in cancer cells derived- exosomes. After the engulfment of the hTERT transcript into fibroblasts, it is translated into a fully active enzyme. Telomerase activity in the recipient, otherwise telomerase negative cells, provides them with a survival advantage. Here we show that exosomal telomerase plays a role in modifying normal fibroblasts into cancer associated fibroblasts (CAFs) by upregulating aSMA and Vimentin, two CAF markers. We also show that telomerase activity changes the transcriptome of microRNA in these fibroblasts. By ectopically expressing microRNA 342, one of the top identified microRNAs we show that it may mediate the proliferative phenotype that these cells acquire upon taking-up exosomal hTERT, providing them with a survival advantage.
CLL is characterized by gradual accumulation of mature appearing long-lived lymphocytes that travel in blood and reside in lymph nodes, spleen and bone marrow. In these sites, pro inflammatory humoral factors support the survival and proliferation of the neoplastic cells. Previous studies showed that levels of the proinflammatory cytokine IL-6 are at least 10 folds higher in patients with CLL compared with healthy individuals. Yet, which cells produce and secrete IL-6 and what triggers this cellular activity in CLL is unknown. Secreted by all types of cells, exosomes are nano-scaled particles that travel in blood and carry a cargo that at least partially reflects the molecular makeup of its cell of origin. Exosomes, including those originating from neoplastic cells, function as stable intercellular transport vehicles that deliver their cargo to cells that engulf them. For example, CLL-derived exosomes are taken up by mesenchymal stromal cells, transforming them to cancer associated fibroblasts. Given the appropriate stimulation, endothelial cells produce IL-6 which provides CLL cells with a survival advantage. Therefore, we hypothesized that CLL-exosomes turn endothelial cells into "IL-6-secreting cells". To test this hypothesis, we transfected vein-derived (HUVECs) and arterial-derived (HAOEC) endothelial cells with exosomes that we isolated from the peripheral blood of 45 treatment naïve patients. We found that endothelial cells take-up CLL-exosomes in a dose- and time- dependent manner. Since CLL cells are protected from apoptosis in IL-6 rich environment, we wondered whether CLL-exosomes turn endothelial cells into IL-6-producing cells. To test this, we exposed endothelial cells to CLL-exosomes and found 50% increase in IL-6 levels, suggesting that the endothelial-exposed cells produced and secreted IL-6. Subsequently, we filtered out this growth medium and added CLL cells to this IL-6 enriched medium. After 15 minutes, STAT3 became phosphorylated and there was 40% decrease in the rate of apoptosis, indicating that IL-6 activated STAT3-dependent anti-apoptotic pathway. Phosphor-proteomics analysis of endothelial cells that were loaded with CLL-exosomes revealed 23 phosphor-proteins that were upregulated. Network analysis unraveled the central role of phosphor-b-catenin. To test whether b-catenin induces IL-6 in these cells, we transfected HUVECs with a b-catenin containing plasmid. We found by ELISA 30% increase in the levels of IL-6 in the culture medium and by chromatin immunoprecipitation assay an increased binding of 3 transcription factors (NFkB, LEF/TCF, and CEBP) to the IL-6 promoter. Taken together, we found that CLL cells communicate with endothelial cells through exosomes that they release. Once these exosomes are taken up by endothelial, they turn them into IL-6 producing cells, which in turn contributes to CLL cells' survival. Disclosures No relevant conflicts of interest to declare.
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