Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Nature. 2012 Jul 26;487(7408):510-3. doi: 10.1038/nature11217.
Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases. Although these cells are extraordinarily rare, they may identify cellular pathways contributing to the blood-borne dissemination of cancer. Here, we adapted a microfluidic device for efficient capture of CTCs from an endogenous mouse pancreatic cancer model and subjected CTCs to single-molecule RNA sequencing, identifying Wnt2 as a candidate gene enriched in CTCs. Expression of WNT2 in pancreatic cancer cells suppresses anoikis, enhances anchorage-independent sphere formation, and increases metastatic propensity in vivo. This effect is correlated with fibronectin upregulation and suppressed by inhibition of MAP3K7 (also known as TAK1) kinase. In humans, formation of non-adherent tumour spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signalling in 5 out of 11 cases. Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.
循环肿瘤细胞（CTCs）从原发性肿瘤脱落到血液中，其中包括引发远端转移的假定前体。尽管这些细胞极为罕见，但它们可能鉴定出有助于癌症血源性传播的细胞途径。在这里，我们从内源性小鼠胰腺癌模型中适应了一种微流控设备，以有效地捕获 CTC，并对 CTC 进行单分子 RNA 测序，鉴定出 Wnt2 是 CTC 中富集的候选基因。在胰腺癌细胞中表达 WNT2 可抑制失巢凋亡，增强锚定非依赖性球体形成，并增加体内转移倾向。这种作用与纤连蛋白的上调相关，并可被 MAP3K7（也称为 TAK1）激酶抑制所抑制。在人类中，胰腺癌细胞形成不贴壁肿瘤球体与多个 WNT 基因的上调相关，并且在 11 例中的 5 例中，胰腺 CTC 显示 WNT 信号通路富集。因此，对 CTC 的分子分析可能鉴定出候选治疗靶点，以防止癌症的远端扩散。
