Prostate cancer that has spread to bone doesn’t completely respond to the standard androgen- targeting therapies. Rather, it tends to progress into castration-resistant prostate cancer (CRPC), which is fatal. The extracellular matrix protein tenascin-C (TNC) facilitates bone metastasis of prostate cancer, and the androgen receptor variant-AR-V7 is associated with treatment-resistant CRPC, but the potential interactions between these proteins remain unclear. To learn more, a new study examined TNC signaling and AR-V7 regulation in 3D tissue cultures called organoids. In the organoids, the interaction of prostate cancer cells with bone precursor cells (preosteoblasts) upregulated both TNC and AR-V7 expression, and this effect was enhanced by the anti-androgen drug enzalutamide. Further experiments on prostate cancer cells revealed that TNC regulates AR-V7 splicing, protein stability, and nuclear localization by activating the Src signaling pathway. In turn, activated Src and AR-V7 upregulated TNC gene expression in the cancer cells. Although more work is needed, the results reveal how prostate cancer cell interaction with the bone microenvironment regulates AR-V7-related treatment resistance and indicate that TNC and Src may be promising therapeutic targets for bone-metastatic prostate cancer and CRPC.