Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast cancer.
Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast cancer.
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DOI：
10.1007/s10585-022-10185-4
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发表时间：
2022-12
影响因子：
4
通讯作者：
Shea, Lonnie D.
中科院分区：
文献类型：
--
作者：
Orbach, Sophia M.;Brooks, Michael D.;Zhang, Yining;Campit, Scott E.;Bushnell, Grace G.;Decker, Joseph T.;Rebernick, Ryan J.;Chandrasekaran, Sriram;Wicha, Max S.;Jeruss, Jacqueline S.;Shea, Lonnie D.
早期转移微环境的变化可用于确定治疗靶点，以抑制继发性肿瘤形成并改善疾病结果。我们使用单细胞 RNA 测序剖析了转移性三阴性乳腺癌模型中正在发展的肺转移生态位。在肿瘤接种后7、14或21天分别对应于转移前、微转移和转移生态位的小鼠中提取肺。转移生态位的进展以中性粒细胞浸润的增加（第 0 天细胞的 5% 到第 21 天细胞的 81%）和与癌症特征相对应的信号通路的增加为标志。重要的是，转移前和早期转移生态位由具有抗癌表型的免疫细胞组成，传统上与转移性疾病无关。正如预期的那样，转移生态位表现出促癌表型。从抗癌表型到促癌表型的转变与这些时间点的中性粒细胞和单核细胞行为直接相关。预测的代谢、转录因子和受体-配体信号传导表明，中性粒细胞的变化可能诱导其他免疫细胞的转变。从转移前微环境中提取的细胞产生的条件培养基成功地抑制了体外肿瘤细胞的增殖和迁移，而体内转移前中性粒细胞和单核细胞的消耗使生存结果恶化，从而验证了正在发展的微环境的抗癌表型。与早期抗癌反应相关的基因可以作为生物标志物，作为治疗早期转移性疾病的靶标。此类疗法有可能彻底改变转移性乳腺癌的临床结果。
Microenvironmental changes in the early metastatic niche may be exploited to identify therapeutic targets to inhibit secondary tumor formation and improve disease outcomes. We dissected the developing lung metastatic niche in a model of metastatic, triple-negative breast cancer using single-cell RNA-sequencing. Lungs were extracted from mice at 7-, 14-, or 21 days after tumor inoculation corresponding to the pre-metastatic, micro-metastatic, and metastatic niche, respectively. The progression of the metastatic niche was marked by an increase in neutrophil infiltration (5% of cells at day 0 to 81% of cells at day 21) and signaling pathways corresponding to the hallmarks of cancer. Importantly, the pre-metastatic and early metastatic niche were composed of immune cells with an anti-cancer phenotype not traditionally associated with metastatic disease. As expected, the metastatic niche exhibited pro-cancer phenotypes. The transition from anti-cancer to pro-cancer phenotypes was directly associated with neutrophil and monocyte behaviors at these time points. Predicted metabolic, transcription factor, and receptor-ligand signaling suggested that changes in the neutrophils likely induced the transitions in the other immune cells. Conditioned medium generated by cells extracted from the pre-metastatic niche successfully inhibited tumor cell proliferation and migration in vitro and the in vivo depletion of pre-metastatic neutrophils and monocytes worsened survival outcomes, thus validating the anti-cancer phenotype of the developing niche. Genes associated with the early anti-cancer response could act as biomarkers that could serve as targets for the treatment of early metastatic disease. Such therapies have the potential to revolutionize clinical outcomes in metastatic breast cancer.
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影响因子：
4.3
作者：
Blomberg OS;Spagnuolo L;de Visser KE
通讯作者：
de Visser KE
影响因子：
3.6
作者：
Decker, Joseph T.;Kandagatla, Pridvi;Jeruss, Jacqueline S.
通讯作者：
Jeruss, Jacqueline S.
影响因子：
48
作者：
Browaeys, Robin;Saelens, Wouter;Saeys, Yvan
通讯作者：
Saeys, Yvan
影响因子：
14
作者：
Bushnell GG;Orbach SM;Ma JA;Crawford HC;Wicha MS;Jeruss JS;Shea LD
通讯作者：
Shea LD
影响因子：
18.4
作者：
Böttcher JP;Reis e Sousa C
通讯作者：
Reis e Sousa C