title: The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma.
abstract: The 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 tRNAiMetwithin 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 tRNAiMetgene. We show that increased tRNAiMetin 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.
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland j.norman@beatson.gla.ac.uk Joanna.Birch@glasgow.ac.uk.
authors.forename: Joanna
authors.initials: J
authors.lastname: Birch
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Cassie J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Kirsteen
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Louise
authors.initials: L
authors.lastname: Mitchell
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Dritan
authors.initials: D
authors.lastname: Liko
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Douglas
authors.initials: D
authors.lastname: Strathdee
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Neilson
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, Scotland j.norman@beatson.gla.ac.uk Joanna.Birch@glasgow.ac.uk.
authors.forename: Jim C
authors.identifier: http://orcid.org/0000-0002-0098-3014
authors.initials: JC
authors.lastname: Norman
keywords: Cell migration; Extracellular matrix; Integrin; Invasion; Melanoma; Metastasis; RNA polymerase III (Pol III); tRNA repertoire; tRNAiMet