Interferon Induces Lineage Plasticity Of Castration-Resistant Prostate Cancer

Prostate cancer (PCa) remains to be the leading cause of cancer incidence in men of the United States. Up to date, androgen deprivation therapy (ADT) remained to be the primary strategy for advanced PCa. Despite drugs targeting androgen receptor (AR) are initially effective for PCa, the disease ultimately recurs to the end stage of castration-resistant PCa (CRPC) that often exhibits neuroendocrine phenotypes, suggesting lineage plasticity is involved in CRPC progression. Emergence of cancer stem cells (CSCs) is highly correlated with the lethal phenotypes; the involvement of PCSCs could explain the resistance of CRPC to chemotherapy or radiotherapy. Therefore, elucidating the mechanisms underlying the acquisition of lineage plasticity in prostate cancer (PCSC) is critical for establish the therapeutic strategy targeting the variant types of CRPC. Based on RNA-seq data from a panel of PCa cells with neuroendocrine phenotypes, interferon (IFN) pathway, such as signal transducer and activator of transcription 1 (STAT1), is highly elevated. Clinical observations have found significantly elevated serum IFN levels in PCa patients after ADT and/or irradiation. Meanwhile, IFN-related DNA damage resistance signature (IRDS) encompassed a subset of STAT1-driven genes with pro-survival functions are known to responsible for intrinsic resistance to chemotherapy and radiotherapy in many malignancies. Altogether, we determined to investigate the involvement of STAT1 signaling in the lineage plasticity of CRPC. We applied tumor sphere assay to study the self-renewal capacity of PCSCs in vitro and subcutaneous injection model to examine tumor incidence and tumor growth in vivo. We observed that IRDS and STAT1-driven genes are significantly upregulated in metastatic tumor specimens of PCa patients and CRPC lines acquired lineage plasticity. Inhibition of JAK-STAT1 by specific small molecule inhibitors such as Ruxolitinib or Fludarabine significantly suppresses the self-renewal capacity of CSC spheres in vitro, and attenuates tumor growth in vivo. In particular, we demonstrated that IFIT5, a bona fide IFN inducible gene, appears to be the key molecule in facilitating the acquisition of stemness properties in PCSCs via regulating Bmi1, Sox2 and Nanog through targeting the turnover of miR-128 and miR-101. In addition, loss of IFIT5 attenuates sphere forming ability in vitro, and decreases tumor incidence in vivo. Moreover, IFIT5, STAT1 and several IRDS genes are highly expressed in CRPC lines with neuroendocrine features when compared to adenocarcinoma lines, suggesting association of STAT1 activation with the lineage plasticity of CRPC. Overall, we demonstrated the impact of STAT1 signaling-induced IFIT5-mediated microRNA turnover on the acquisition of stemness properties of PCSCs. The outcome of this study may provide a novel therapeutic strategy for managing the therapy-resistant CRPC. Citation Format: U-Ging Lo, Yu-An Chen, Ping Mu, Ho Lin, Chih-Ho Lai, Jer-Tsong Hsieh. Interferon induces lineage plasticity of castration-resistant prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6028.