Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases
Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases
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DOI：
10.1093/neuonc/noab002
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发表时间：
2021-01-12
期刊：
影响因子：
15.9
通讯作者：
Siegel, Peter M.
中科院分区：
文献类型：
--
作者：
Dankner, Matthew;Caron, Maxime;Siegel, Peter M.
背景60%的手术切除的脑转移瘤（BrM）在1年内复发。长期以来，这些复发被认为是手术期间癌细胞扩散的结果。我们检验了另一种假设，即癌细胞侵入邻近脑组织在局部复发和总生存期缩短中起着重要作用。我们确定了164例手术切除的乳腺癌的侵袭模式，并与局部复发和总生存率相关。我们对来自BrM和邻近脑组织的> 15，000个细胞进行了单细胞RNA测序（scRNAseq）。用一组新的BrM患者来源的异种移植物（PDX）和患者组织进行靶点验证。我们证明转移性癌细胞侵入邻近脑与局部复发和总生存期缩短有关。配对肿瘤和邻近脑样品的scRNAseq证实了肿瘤邻近脑中存在侵袭性癌细胞。对这些细胞的分析鉴定了与位于转移灶内的癌细胞相比，侵袭性癌细胞中的冷诱导RNA结合蛋白（CIRBP）过表达。应用PDX模型，概括了在患者中观察到的侵袭模式，我们表明CIRBP在高度侵袭性的BrM中过表达，并且是脑中有效侵袭性生长所必需的。这些数据表明，肿瘤周围浸润作为BrM治疗失败的驱动因素，在功能上由CIRBP介导。这些发现提高了我们对术后治疗失败的生物学基础的理解，并为基于手术切除的BrM的侵袭模式的合理临床试验开发奠定了基础。
Background. Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.Methods. We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues.Results. We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain.Conclusions. These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.