MALAT1 has previously been described as a metastasis-promoting long non-coding RNA (lncRNA). Unexpectedly, we found that targeted inactivation of the Malat1 gene without altering the expression of its adjacent genes in a transgenic mouse model of breast cancer promoted lung metastasis, and importantly, this phenotype was reversed by genetic add-back of Malat1 . Similarly, knockout of MALAT1 in human breast cancer cells induced their metastatic ability, which was reversed by Malat1 re-expression. Conversely, overexpression of Malat1 suppressed breast cancer metastasis in transgenic, xenograft, and syngeneic models. Mechanistically, MALAT1 binds and inactivates the pro-metastatic transcription factor TEAD, blocking TEAD from associating with its co-activator YAP and target gene promoters. Moreover, MALAT1 levels inversely correlate with breast cancer progression and metastatic ability. These findings demonstrate that MALAT1 is a metastasis-suppressing lncRNA rather than a metastasis promoter in breast cancer, calling for rectification of the model for a highly abundant and conserved lncRNA.

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.

MicroRNAs (miRNAs) are small non-coding RNAs regulating post-transcriptional gene expression. They play important roles in many biological processes under physiological or pathological conditions, including development, metabolism, tumorigenesis, metastasis, and immune response. Over the past 15 years, significant insights have been gained into the roles of miRNAs in cancer. Depending on the cancer type, miRNAs can act as oncogenes, tumor suppressors, or metastasis regulators. In this review, we focus on the role of miRNAs as components of molecular networks regulating metastasis. These miRNAs, termed metastamiRs, promote or inhibit metastasis through various mechanisms, including regulation of migration, invasion, colonization, cancer stem cell properties, epithelial-mesenchymal transition, and microenvironment. Some of these metastamiRs represent attractive therapeutic targets for cancer treatment.