Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages.
Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages.
复制标题
结直肠癌细胞中依赖受体CSF1R的沉默激活肿瘤相关巨噬细胞
DOI：
10.1136/jitc-2022-005610
复制
发表时间：
2022-12
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
刺激性因子1受体（CSF1R）是一种经典的酪氨酸激酶受体，已被鉴定为多种癌症中的原始癌基因。 CSF1/CSF1R轴对于M2-型肿瘤相关巨噬细胞（M2 TAM）的存活和分化至关重要。但是，我们在这里发现，在结直肠癌（CRC）中，CSF1R表达异常下调，其生物学功能和潜在的机制在CRC进展中变得难以捉摸。
使用癌症基因组图集和基因表达综合数据集进入CRC和正常肠粘膜中III类受体酪氨酸激酶的表达，并通过我们的经过测试的队列进一步验证。在CRC细胞中重建CSF1R，以在体外和体内识别其生物学功能。我们比较了CSF1R表达和CRC细胞和巨噬细胞之间的甲基化差异。此外，使用共培养系统来模仿CSF1R过表达的CRC细胞和M2样巨噬细胞之间的竞争机制。我们利用CSF1R抑制剂PLX3397消融M2 TAM，并评估了其在动物模型中CRC治疗方面的疗效。
我们在这里发现，CSF1R在CRC中被沉默，并且可以通过caspases裂解受体在CRC细胞中的表达，并在体外和体内限制肿瘤的生长，充当肿瘤抑制基因。我们进一步将CSF1R确定为一种新型依赖受体，它具有起作用的肿瘤抑制基因或癌基因的潜力，具体取决于其活化状态。在CRC肿瘤中，CSF1R表达富含TAM，其表达与ITH CRC患者的预后不良有关。在共培养系统中，表达CSF1R的CRC细胞与M2样巨噬细胞竞争CSF1R配体，从而导致巨噬细胞中CSF1R激活和细胞增殖的降低。 PLX3397阻止CSF1R可以耗尽M2 TAM并增加CD8+ T细胞浸润，有效抑制肿瘤的生长和转移，并改善对化学疗法和免疫疗法的反应。
我们的发现表明，CSF1R是一种新型鉴定的依赖受体，使CRC沉默。沉默使其配体刺激在M2 TAM上表达的CSF1R，这是M2 TAM耗竭和CRC治疗的有吸引力的治疗靶标。
Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression. The expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functions in vitro and in vivo. We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models. We found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growth in vitro and in vivo, functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8+ T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy. Our findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment.
登录
查看更多内容
影响因子：
7.7
作者：
Duplaquet, Leslie;Leroy, Catherine;Tulasne, David
通讯作者：
Tulasne, David
影响因子：
12.4
作者：
Muñoz-Garcia J;Cochonneau D;Télétchéa S;Moranton E;Lanoe D;Brion R;Lézot F;Heymann MF;Heymann D
通讯作者：
Heymann D
影响因子：
10.9
作者：
Cannarile MA;Weisser M;Jacob W;Jegg AM;Ries CH;Rüttinger D
通讯作者：
Rüttinger D
影响因子：
37.3
作者：
Montor WR;Salas AROSE;Melo FHM
通讯作者：
Melo FHM
影响因子：
82.9
作者：
通讯作者：
--