Abstract
Metabolic changes within the cell and its niche affect cell fate and are involved in many diseases and disorders including cancer and viral infections. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS). KSHV latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, these miRNAs are responsible for inducing the Warburg effect in infected cells. Here we identify a novel mechanism enabling KSHV to manipulate the metabolic nature of the tumour microenvironment. We demonstrate that KSHV infected cells specifically transfer the virus-encoded microRNAs to surrounding cells via exosomes. This flow of genetic information results in a metabolic shift toward aerobic glycolysis in the surrounding non-infected cells. Importantly, this exosome-mediated metabolic reprogramming of neighbouring cells supports the growth of infected cells, thereby contributing to viral fitness. Finally, our data show that this miRNA transfer-based regulation of cell metabolism is a general mechanism used by other herpesviruses, such as EBV, as well as for the transfer of non-viral onco-miRs. This exosome-based crosstalk provides viruses with a mechanism for non-infectious transfer of genetic material without production of new viral particles, which might expose them to the immune system. We suggest that viruses and cancer cells use this mechanism to shape a specific metabolic niche that will contribute to their fitness.
Highlights
Altered metabolism is regarded as a hallmark of cancer
The gamma-herpesviruses Kaposi’s Sarcoma Associated Herpesvirus (KSHV) is a viral agent associated with a large number of human malignancies
We have recently shown that the Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded microRNAs induce aerobic glycolysis in infected cells through regulation of key cellular genes involved in mitochondrial activity and regulation of glucose metabolism [11]
Summary
Altered metabolism is regarded as a hallmark of cancer. It is thought that cancer cells rewire metabolic pathways in such a way that biosynthetic processes are balanced against ATP production to support high rates of proliferation [1]. Despite the inefficiency of glycolysis in energy production, the glycolytic phenotype provides cancer cells with several advantages such as increased biosynthesis of intermediate macromolecules and anti-apoptosis and signalling through metabolites [2]. It has been suggested that cancer cells, in addition to their intrinsic metabolic alteration can induce aerobic glycolysis in adjacent stromal cells, a phenomenon termed the ‘reverse Warburg Effect’ [3, 4]. The reverse Warburg effect emphasises the importance of tumour stromal cells in supplying energy metabolites and chemical building blocks to the rapidly proliferating cancer cells
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