Abstract
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 (ITGB3), which promotes enhanced migration and invasion. Bioinformatic analysis and subsequent experimentation revealed an enrichment of RNA metabolism pathways that stabilize ITGB3 transcripts. Specifically, the RNA binding protein heterogeneous nuclear ribonucleoprotein L (HNRNPL), whose expression is regulated by Nrf2, mediates the formation of circular RNAs that sponge the family of let-7 microRNAs that target ITGB3. Collectively, our findings identify a mechanism of radiation-induced metastasis that is driven by alterations in RNA metabolism.