细胞脱离胞外基质（失巢）后继续存活是肿瘤转移的前提，除外凋亡耐受，其他死亡方式异常亦参与其中。我们发现：失巢前列腺癌（PCa）细胞发生铁死亡，部分细胞通过细胞迁移诱导蛋白（CEMIP）上调溶质载体蛋白SLC1A5表达而抑制铁死亡。提出“CEMIP通过SLC1A5增强谷氨酰胺摄取、降低脂质过氧化水平而诱导失巢PCa细胞铁死亡抵抗”的科学假说。本项目拟以失巢PCa细胞及雄性裸鼠转移瘤模型为研究对象，应用流式细胞术、活体动物显像等技术观察CEMIP抑制细胞铁死亡、促进肿瘤转移的现象；以蛋白激酶MAPK和转录因子ATF4为切入点，应用蛋白质谱学、元素示踪技术、蛋白及染色质免疫共沉淀等，明确CEMIP/ATF4上调SLC1A5表达、诱导铁死亡抵抗的效应机制；以临床病例和数据库信息为依据，验证假说并筛选相关标志物。本研究有望揭示PCa转移的新机制，为预防和治疗转移性PCa提供新策略和思路。

Long-term survival during extracellular matrix (ECM) detachment is a crucial early event for cancer metastasis cascade. Emerging evidences have illustrated that resistance to anoikis-independent cell death may involve in this procedure. Previously, we have found that ferroptosis, an iron-dependent form of nonapoptotic oxidative cell death, was evoked to eliminate ECM-detached prostate cancer cells while ferroptosis resistance was induced by cell migration inducing protein (CEMIP) through upregulated the expression of solute carrier family 1 member 5 (SLC1A5) in those survival cells. Based on our preliminary data, we hypothesize that over-expression of CEMIP may upregulate expression of SLC1A5, thus promote glutamine uptake, inhibit lipid peroxidation and consequently, induce ferroptosis resistance in the more aggressive prostate cancer cells during ECM detachment. The current proposed project aims to reveal the correlation between detachment-induced ferroptosis and cell survival, and to elucidate the precise effects of CEMIP/ATF4/SLC1A5 pathway in compromising ferroptosis by increasing glutamine uptake and inhibiting lipid peroxidation. Flow cytometry and optical in vivo imaging techniques will be used to evaluate the impact of CEMIP on ferroptosis resistance and metastasis potentials in detachment-resistance prostate cancer cell model and experimental metastasis animal model (tail vein injection of male nude mouse). In addition, protein profiling, isotope tracing, protein immunoprecipitation (CoIP), chromatin immunoprecipitation (ChIP) and some other state-of the-art techniques will be adopted to uncover the precise molecular mechanisms underlying the bioeffects of CEMIP/ATF4 on augmentation of SLC1A5 expression and induction of ferroptosis resistance in detached prostate cancer cells. Further, clinical information and several cancer related databases will be employed to confirm our hypothesis and to screen potential biomarkers for prostate cancer metastasis and prognosis prediction. To summarize, the ultimate purpose of the current study is to clarify the role of enhancing glutamine uptake by CEMIP in boosting ferroptosis resistance and to provide new strategies and ideas for prevention and treatment of metastatic prostate cancer.