Lombardi Olivia, Li Ran, Jabbar Faiz, Evans Hannah, Halim Silvia, Lima Joanna D C C, Browning Lisa, Byrne Helen M, Choudhry Hani, Ratcliffe Peter J, Mole David R
NDM Research Building, University of Oxford, Old Road Campus, Headington, Oxford OX3 7FZ, UK.
NDM Research Building, University of Oxford, Old Road Campus, Headington, Oxford OX3 7FZ, UK; Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus, Headington, Oxford OX3 7DQ, UK.
Cell Rep. 2025 Jan 28;44(1):115169. doi: 10.1016/j.celrep.2024.115169. Epub 2025 Jan 9.
Clear cell kidney cancers are characterized both by conserved oncogenic driver events and by marked intratumor genetic and phenotypic heterogeneity, which help drive tumor progression, metastasis, and resistance to therapy. How these are reflected in transcriptional programs within the cancer and stromal cell components remains an important question with the potential to drive novel therapeutic approaches to treating cancer. To better understand these programs, we perform single-cell transcriptomics on 75 multi-regional biopsies from kidney tumors and normal kidney. We identify conserved patterns of transcriptional dysregulation and their upstream regulators within the tumor and associated vasculature. We describe recurrent subclonal transcriptional consequences of Chr14q loss linked to metastatic potential. We identify prognostically significant conserved patterns of intratumor transcriptional heterogeneity. These reflect co-existing cell states found in both cancer cells and normal kidney cells, indicating that rather than arising from genetic heterogeneity they are a consequence of lineage plasticity.
透明细胞肾癌的特征在于存在保守的致癌驱动事件以及显著的肿瘤内基因和表型异质性，这些因素有助于推动肿瘤进展、转移和对治疗的抗性。这些特征如何在癌症和基质细胞成分的转录程序中体现，仍然是一个重要问题，有可能推动治疗癌症的新方法。为了更好地理解这些程序，我们对来自肾肿瘤和正常肾脏的75份多区域活检样本进行了单细胞转录组学分析。我们在肿瘤及相关脉管系统中确定了转录失调的保守模式及其上游调节因子。我们描述了与转移潜能相关的14号染色体长臂缺失的复发性亚克隆转录后果。我们确定了肿瘤内转录异质性在预后方面具有显著意义的保守模式。这些反映了在癌细胞和正常肾细胞中同时存在的细胞状态，表明它们并非源于基因异质性，而是谱系可塑性的结果。
