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 cancer patients. 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 (TNBC) and established that radiation resistant tumor cells have enhanced metastatic capacity, especially to bone. Resistance to radiation increases the expression of integrin b3 (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 heterogenous nuclear ribonucleoprotein L (HNRNPL), whose expression is regulated by Nrf2, mediates the formation of circular RNAs (circRNAs) that function as competing endogenous RNAs (ceRNAs) for the family of let-7 microRNAs that target ITGb3. Collectively, our findings identify a novel mechanism of radiation-induced metastasis that is driven by alterations in RNA metabolism. Two biological replicates of radiation resistant MDA-MB-468 human breast cancer cell line with and without stable HNRNPL knockdown were sequenced on Nanopore using Induro-mediated circular RNA-sequencing to identify HNRNPL-dependent circular RNA.