肿瘤干细胞分泌的SAA1通过TLR2/4介导的肺腺癌细胞干性转化促进肿瘤恶性发展的机制研究

肺腺癌具有瘤内异质性，肿瘤细胞可被分为不同亚群，分化状态较低的肿瘤干细胞亚群（CSCs）与肿瘤发生、发展、治疗抵抗和复发转移高度相关，因此探索CSCs的细胞生物学和分子生物学特征有重要意义。.本课题组在前期构建的原代肺腺癌细胞实验模型中识别并分选了肺腺癌CSCs。转录组测序提示，CSCs有异常激活的炎症信号通路，并且炎症相关蛋白SAA1异常高表达于CSCs亚群。我们初步报道CSCs来源的SAA1信号促进肺腺癌细胞干性转化，并可导致肺腺癌的恶性进展和治疗抵抗。机制上，我们初步发现SAA1依赖于TLR2/4影响相关恶性表型。由上我们提出假说：肿瘤干细胞分泌的SAA1依赖TLR2/4激活炎症信号通路介导肺腺癌细胞的干性转化并促进肿瘤恶性进展和治疗抵抗。.本课题拟研究微环境中肿瘤干细胞来源的SAA1对肺腺癌细胞干性转化和恶性进展的作用及其下游分子机制，最终为肺腺癌的诊疗提供新思路。

Cell subpopulations exist in lung adenocarcinoma (LUAD) due to the intra-tumor heterogeneity, the most primitive subpopulation cancer stem cells (CSCs) have great contributions to cancer initiation, progression, therapeutic resistance, cancer relapse and metastasis. Thus, understanding the biological and molecular hallmarks of CSCs represents great interesting in the field..We identified and sorted CSCs from our previously established patients derived primary lung adenocarcinoma cells（PDLACs）experimental system by flow cytometry. Our transcriptome sequencing data indicated that, the CSCs have abnormally activated inflammatory signal, and inflammatory protein SAA1 was significantly upregulated in CSCs. We found SAA1 promotes cancer stemness transformation that leads to malignant progression and treatment resistance in LUAD. Mechanically, we found that the biological impact of SAA1 in LUAD dependents on TLR2/4. Thus, we rise our hypothesis: CSCs secreted SAA1 induces cancer stemness transformation via TLR2/4 mediated inflammation, and the stemness transformation promotes malignant progression in LUAD..In current grant proposal we would validate the biological impact of CSCs secreted SAA1 on stemless transformation and malignant progression in LUAD and explore the downstream mechanisms, which could rise new ideas for LUAD clinical practice.