Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial–mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ–ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.
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- Invasion–metastasis cascade
A stepwise succession of events whereby primary tumour cells adopt a phenotype that promotes local invasion, intravasation into the bloodstream, extravasation and migration to distant organ sites, and colonization of those sites, which often involves physiological adaptation.
- Long noncoding RNAs
(lncRNAs). Noncoding RNA transcripts longer than 200 nucleotides, which are frequently polyadenylated, and that show no evidence that they encode proteins.
- Competing endogenous RNAs
(ceRNAs). RNA transcripts (which may be lncRNAs, mRNAs or pseudogenes) that are capable of binding and influencing the activity of microRNAs through complementary base pairing.
- Organ-specific tropism
The propensity for disseminated cancer cells to colonize and proliferate at specific organ sites due to diverse physiological and molecular factors.
- Antisense oligonucleotides
(ASOs). Exogenous oligonucleotides, often chemically modified to resist degradation, that alter the amount, stability or activity of complementary RNA transcripts, usually through RNase-based mechanisms.
- Epithelial–mesenchymal transition
(EMT). A set of molecular processes that convert cancer cells of polarized epithelial phenotypes into more invasive mesenchymal phenotypes.
A subtype of programmed cell death triggered by inappropriate cellular or extracellular matrix interactions, often in the setting of tumour cells escaping their primary environment.
Collections of metastasized tumour cells that are clinically detectable but typically under 2 mm in diameter in human patients.
- Comprehensive identification of RNA-binding proteins by mass spectrometry
(ChIRP-MS). A method of identifying endogenous RNA–protein interactions with high specificity, using in vivo crosslinking, RNA pulldown and mass spectrometry.
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Liu, S.J., Dang, H.X., Lim, D.A. et al. Long noncoding RNAs in cancer metastasis. Nat Rev Cancer (2021). https://doi.org/10.1038/s41568-021-00353-1