医科院肿瘤医院：肿瘤相关巨噬细胞的XBP1活化可促进结直肠癌进展
- ①结直肠癌浸润的肿瘤相关巨噬细胞（TAM）表现出XBP1的剪接及活化；
- ②TAM中的XBP1活化可促进结直肠癌的生长及转移；
- ③敲除XBP1可调节TAM的细胞因子表达谱，抑制促肿瘤细胞因子（IL-4、IL-6、VEGFA等）的表达，并增加TNF-α的表达；
- ④敲除XBP1可抑制SIRPα及THBS1的表达，以阻断“别吃我”信号，从而促进巨噬细胞的吞噬作用；
- ⑤基于CRISPR敲除XBP1（利用AAV2表达靶向XBP1的sgRNA），可增强TAM的抗肿瘤活性。
主编推荐语
中国医学科学院肿瘤医院的朱红霞团队与徐宁志团队在Signal Transduction and Targeted Therapy上发表的一项最新研究结果，发现在结直肠癌患者的肿瘤相关巨噬细胞中，可观察到XBP1的剪接及活化。机制上，XBP1活化可通过上调促肿瘤细胞因子的表达，并通过增强CD47/SIRPα信号以抑制巨噬细胞的吞噬作用，从而促进结直肠癌的生长及转移。利用CRISPR敲除XBP1，可增强肿瘤相关巨噬细胞的抗肿瘤活性。该研究结果提示，靶向XBP1信号可作为治疗结直肠癌的潜在策略。
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XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer
在人结直肠癌中，XBP1调节肿瘤相关巨噬细胞的促肿瘤功能
10.1038/s41392-021-00761-7
2021-10-20, Article
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Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206 TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking "don't eat me" recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.
First Authors:
Yahui Zhao
Correspondence Authors:
Ningzhi Xu,Hongxia Zhu
All Authors:
Yahui Zhao,Weina Zhang,Miaomiao Huo,Peng Wang,Xianghe Liu,Yu Wang,Yinuo Li,Zhixiang Zhou,Ningzhi Xu,Hongxia Zhu
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