头颈部鳞状细胞癌
转移
免疫系统
CD8型
生物
癌症研究
细胞
相互作用体
医学
头颈部癌
癌症
免疫学
基因
内科学
生物化学
遗传学
作者
Hong Sheng Quah,Elaine Yiqun Cao,Lisda Suteja,Constance H. Li,Hui Sun Leong,Fui Teen Chong,Shilpi Gupta,Camille Arcinas,John F. Ouyang,Vivian Ang,Teja Celhar,Yunqian Zhao,Hui Chen Tay,Jerry K. Y. Chan,Takeshi Takahashi,Daniel S.W. Tan,Subhra K. Biswas,Owen J. L. Rackham,N. Gopalakrishna Iyer
标识
DOI:10.1038/s41467-023-37379-y
摘要
Profiling tumors at single-cell resolution provides an opportunity to understand complexities underpinning lymph-node metastases in head and neck squamous-cell carcinoma. Single-cell RNAseq (scRNAseq) analysis of cancer-cell trajectories identifies a subpopulation of pre-metastatic cells, driven by actionable pathways including AXL and AURK. Blocking these two proteins blunts tumor invasion in patient-derived cultures. Furthermore, scRNAseq analyses of tumor-infiltrating CD8 + T-lymphocytes show two distinct trajectories to T-cell dysfunction, corroborated by their clonal architecture based on single-cell T-cell receptor sequencing. By determining key modulators of these trajectories, followed by validation using external datasets and functional experiments, we uncover a role for SOX4 in mediating T-cell exhaustion. Finally, interactome analyses between pre-metastatic tumor cells and CD8 + T-lymphocytes uncover a putative role for the Midkine pathway in immune-modulation and this is confirmed by scRNAseq of tumors from humanized mice. Aside from specific findings, this study demonstrates the importance of tumor heterogeneity analyses in identifying key vulnerabilities during early metastasis.
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