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Abstract
ABSTRACTThe cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, the level of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts has been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus, specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis.
Highlights
Many of the steps to metastasis require cancer cells to migrate invasively through the extracellular matrix (ECM) that surrounds tumours and tissues (Sahai, 2005)
As we have previously shown that elevated tRNAiMet levels do not lead to upregulated protein synthesis, increased cell proliferation (Clarke et al, 2016), or altered energy metabolism we looked at the ability of this transfer RNAs (tRNAs) to influence other cell characteristics that are associated with cancer aggressiveness
In this paper we show that elevated levels of tRNAiMet activate a cell migration programme dependent on α5β1 integrin and formation of the translation initiation ternary complex
Summary
Many of the steps to metastasis require cancer cells to migrate invasively through the extracellular matrix (ECM) that surrounds tumours and tissues (Sahai, 2005). Pol III function is controlled by multiple oncogenes and tumour suppressors including c-myc, p53 and Rb, mooting this RNA polymerase as a potential master regulator of a translational programme that contributes to cancer progression (White, 2008). It has been known for some time that expression of certain Pol III target genes, for instance tRNAiMet (the initiator methionine tRNA responsible for recognising the start codon and initiating translation), is upregulated in cancer and it has been proposed that this may drive progression of the disease (PavonEternod et al, 2009, 2013). Rather, increased tRNAiMet alters the fibroblast secretome to favour synthesis and secretion
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