中文摘要：
解析肿瘤中多细胞相互作用如何影响对BRAF和MEK1/2 MAPK抑制剂（MAPKi）的耐药通路仍是一项挑战。为此，我们对来自MAPK驱动型疾病活检样本的肿瘤细胞与基质/免疫细胞之间的全局配体-受体相互作用进行了分析。MAPKi在一些患者中增加了肿瘤相关巨噬细胞（TAMs），这与较差的临床疗效相关；同时，MAPKi通过AXL、MERTK等受体酪氨酸激酶（RTKs）及其配体GAS6，协同放大了肿瘤与TAMs之间的双向信号传导。在异种移植瘤中，活体显微成像同时监测了RTK下游多种激酶的原位单细胞活性，结果显示MAPKi增加了TAMs的数量，并增强了TAMs邻近肿瘤细胞的旁路信号。作为阻断这一信号传导的原理验证策略，我们开发了一种多RTK激酶抑制剂的纳米制剂，该制剂能够在TAMs中蓄积并延缓疾病进展。因此，旁路信号可以在邻近细胞类型之间相互放大，这为治疗策略的设计提供了新的契机。
英文摘要：
Interpreting how multicellular interactions in the tumor affect resistance pathways to BRAF and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via receptor tyrosine kinases (RTKs) including AXL, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.
论文信息：
论文题目：Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy
期刊名称：Science Advances
时间期卷：Vol 6, Issue21(2020)
在线时间：2020年5月22日
DOI: 10.1126/sciadv.aaz85
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes&Control Liposomes
办事处：靶点科技
Clodronate Liposomes氯膦酸盐脂质体清除小鼠乳腺癌模型里巨噬细胞。荷兰Liposoma巨噬细胞清除剂ClodronateLiposomes见刊于Science Advances：利用一种TAM亲和性纳米疗法高效阻断局部相互传递的肿瘤-巨噬细胞信号。
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体清除巨噬细胞的材料和方法：
In vivo macrophage depletion
For clodronate liposome treatment, 150 μl of either clodronate-loaded (5 mg/ml) or PBS-loaded liposomes (Liposoma BV) were injected intraperitoneally on day 1 of the study, followed by 50 μl every 3 days thereafter (until subject reached experimental end point). For α-CSF1R antibody treatment, 200 μg of either InVivoMAb anti-mouse CSF1R (AFS98, BioXCell) or rat immunoglobulin G2a isotype control (2A3¸BioXCell) in 200 μl of PBS was injected intraperitoneally beginning on day 1 of the study, followed by every 2 to 3 days thereafter (until subject reached experimental end point). NanoFore treatments were given by tail vein or intraperitoneal injection upon immediate dilution into final 50 or 200 μl of 1× PBS, respectively.
巨噬细胞清除材料和方法文献截图：利用一种TAM亲和性纳米疗法高效阻断局部相互传递的肿瘤-巨噬细胞信号
