SPHK1通过分泌蛋白MFGE8调控巨噬细胞募集与M2型极化促结直肠癌转移的分子机制

肿瘤细胞与免疫微环境间的动态调控是影响肿瘤转移的关键因素，是目前肿瘤防治的重点和难点。我们预实验结果发现，结直肠癌细胞中SPHK1可能通过分泌蛋白MFGE8，调控肿瘤相关巨噬细胞（TAMs）募集与M2型极化，继而增强肿瘤细胞侵袭与迁移潜能。基于前期工作基础，我们提出SPHK1驱动肿瘤细胞与巨噬细胞动态交互促进结直肠癌转移的科学假说。本研究拟：1.阐明SPHK1通过S1P/S1PR/pSTAT3信号上调MFGE8及MFGE8调控TAMs的分子机制；2.揭示SPHK1/MFGE8驯化的TAMs通过分泌生物活性因子，反作用于肿瘤细胞，促其转移的功能与机制；3.探讨SPHK1抑制剂联合免疫治疗对结直肠癌转移的影响，并结合临床样本，探讨SPHK1及MFGE8与肠癌进展及预后的关系。本研究旨在揭示肿瘤细胞与巨噬细胞间彼此对话、协同促肿瘤转移的新机制，并为结直肠癌预后判断及联合治疗提供新的靶点和策略。

The dynamic regulations between tumor cells and tumor microenvironment play pivotal roles in affecting the metastasis of tumors, which is the focus and difficulty of tumor prevention and treatment. In our previous work, we found that sphingosine kinase 1 (SPHK1) was significantly upregulated in colorectal cancer (CRC) cells and led to upregulation of secreted protein MFGE8. MFGE8 can induce the recruitment and M2-type polarization of tumor-associated macrophages (TAMs), thereby enhancing the potential of tumor cell migration and invasion. Based on our preliminary results, we hypothesize that SPHK1-mediated cross-talks between tumor cells and TAMs could lead to the metastasis of CRC. In this study, we will firstly elucidate the mechanism of SPHK1 in regulating MFGE8 through S1P/S1PR/pSTAT3 signal and the mechanism of MFGE8 in regulating TAMs. Secondly, we will explore the mechanism by which TAMs shaped by SPHK1/MFGE8 secrete biologically active factors to promote the invasion and migration of tumor cells. Thirdly, we will further try to figure out the effect of SPHK1 inhibitor combined with immunotherapy on CRC metastasis, and explore the potential of SPHK1 or MFGE8 as biomarkers of the progression and prognosis of CRC patients. Our study aims to reveal new mechanisms of the mutual domestication between tumor cells and macrophages in promoting CRC metastasis, and provide new targets and strategies for prognosis and treatment of CRC.