Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Urology, West China Hospital, Chengdu, China.
Signal Transduct Target Ther. 2023 Apr 17;8(1):155. doi: 10.1038/s41392-023-01362-2.
Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL) cells. Renal tumors with either VHL or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.
von Hippel-Lindau（VHL）肿瘤抑制基因失活是肾透明细胞癌（ccRCC）的一个标志。该肿瘤抑制基因失活的异质性的重要性尚未得到充分报道。为了研究在人 ccRCC 中观察到的肿瘤内 VHL 异质性的影响，我们在四个 RCC 模型中进行了 VHL 基因缺失的工程改造，包括从侵袭性转移性病例中衍生的新的原发性肿瘤细胞系。与表达 VHL 的亲本（VHL）细胞相比，VHL 基因缺失（VHL-KO）细胞经历上皮间质转化（EMT），表现出更高的迁移能力，但增殖和致瘤能力降低。单独用 VHL 或 VHL-KO 细胞形成的肾肿瘤表现出最小的转移潜力。联合肿瘤显示出猖獗的肺转移，突出了一种新的协同转移机制。增殖能力差的 VHL-KO 细胞刺激邻近的 VHL 细胞的增殖、EMT 和迁移。骨桥蛋白（POSTN）是一种由不表达 VHL（VHL）的细胞过度表达和分泌的可溶性蛋白，通过增强 VHL-WT 细胞的迁移能力和促进肿瘤细胞血管逃逸来促进转移。POSTN 的基因缺失或抗体阻断在我们的临床前模型中显著抑制了肺转移。这项工作支持了一种通过破坏肿瘤内异质细胞群体之间的关键转移串扰来阻止 ccRCC 进展的新策略。
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