Resistance to radiation enhances metastasis by altering RNA metabolism

The cellular programs that mediate therapy resistance are often important drivers of metastasis, a phenomenon that needs to be understood better to improve screening and treatment options for patients with cancer. Although this issue has been studied extensively for chemotherapy, less is known about a causal link between resistance to radiation therapy and metastasis. We investigated this problem in triple-negative breast cancer and established that radiation-resistant tumor cells have enhanced metastatic capacity. Resistance to radiation increases the expression of integrin β3 (<i>ITGB3</i>), which promotes enhanced migration and invasion. Bioinformatic analysis and subsequent experimentation revealed an enrichment of RNA metabolism pathways that stabilize <i>ITGB3</i> transcripts. Specifically, the RNA binding protein heterogeneous nuclear ribonucleoprotein L (<i>HNRNPL</i>), whose expression is regulated by Nrf2, mediates the formation of circular RNAs that sponge the family of let-7 microRNAs that target <i>ITGB3</i>. Collectively, our findings identify a mechanism of radiation-induced metastasis that is driven by alterations in RNA metabolism.