Ogden Samuel, Metic Nasrine, Leylek Ozen, Smith Elise A, Berner Alison M, Baker Ann-Marie, Uddin Imran, Buzzetti Marta, Gerlinger Marco, Graham Trevor, Kocher Hemant M, Efremova Mirjana
Barts Cancer Institute, Queen Mary University of London, London, UK.
The Institute of Cancer Research, London, UK.
Cell Genom. 2025 Jul 9;5(7):100881. doi: 10.1016/j.xgen.2025.100881. Epub 2025 May 19.
Phenotypic heterogeneity and plasticity in colorectal cancer (CRC) has a crucial role in tumor progression, metastasis, and therapy resistance. However, the regulatory factors and the extrinsic signals driving phenotypic heterogeneity remain unknown. Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we reveal cancer cell states with regenerative and inflammatory phenotypes that closely resemble metastasis-initiating cells in mouse models. We identify an intermediate population with a hybrid regenerative and stem phenotype. We reveal the transcription factors AP-1 and nuclear factor κB (NF-κB) as their key regulators and show localization of these states in an immunosuppressive niche both at the invasive edge in primary CRC and in liver metastasis. We uncover ligand-receptor interactions predicted to activate the regenerative and inflammatory phenotype in cancer cells. Together, our findings reveal regulatory and signaling factors that mediate distinct cancer cell states and can serve as potential targets to impair metastasis.
结直肠癌（CRC）中的表型异质性和可塑性在肿瘤进展、转移及治疗耐药性中起着关键作用。然而，驱动表型异质性的调控因子和外在信号仍不清楚。通过结合来自原发性和转移性CRC患者的单细胞多组学和空间转录组学数据，我们揭示了具有再生和炎症表型的癌细胞状态，这些状态与小鼠模型中的转移起始细胞极为相似。我们鉴定出一个具有再生和干细胞混合表型的中间群体。我们揭示转录因子AP-1和核因子κB（NF-κB）是其关键调控因子，并展示了这些状态在原发性CRC侵袭边缘和肝转移的免疫抑制微环境中的定位。我们发现了预计会激活癌细胞中再生和炎症表型的配体-受体相互作用。总之，我们的研究结果揭示了介导不同癌细胞状态的调控和信号因子，这些因子可作为损害转移的潜在靶点。
