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bioRxiv · 10.1101/2025.02.19.638943

Resistance to Radiation Enhances Metastasis by Altering RNA Metabolism

Kumar, A.·Kishimoto, K.·Goel, H. L.·Wisniewski, C.·Li, R.·Pacheco, B.·Zhu, L. J.·Flavahan, W. A.·Mercurio, A. M.
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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 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 {beta}3 (ITG{beta}3), which promotes enhanced migration and invasion. Bioinformatic analysis and subsequent experimentation revealed an enrichment of RNA metabolism pathways that stabilize ITG{beta}3 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 ITG{beta}3. Collectively, our findings identify a novel mechanism of radiation-induced metastasis that is driven by alterations in RNA metabolism.

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Kumar, A., Kishimoto, K., Goel, H. L., Wisniewski, C., Li, R., Pacheco, B., Zhu, L. J., Flavahan, W. A., Mercurio, A. M.. 2025-02-25. Resistance to Radiation Enhances Metastasis by Altering RNA Metabolism. https://doi.org/10.1101/2025.02.19.638943

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