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RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis

机译:胰腺循环肿瘤细胞的RNA测序牵涉WNT信号转移

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摘要

Circulating tumour cells (CTCs) shed into blood from primary cancers include putative precursors that initiate distal metastases~1. 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~2 for efficient capture of CTCs from an endogenous mouse pancreatic cancer model~3 and subjected CTCs to single-molecule RNA sequencing4, 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 upre-gulation 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.
机译:从原发性癌症中渗入血液的循环肿瘤细胞(CTC)包括引发远端转移的推定前体〜1。尽管这些细胞极为稀少,但它们可能会识别有助于血液传播癌症的细胞途径。在这里,我们采用了一种微流体装置〜2来有效捕获内源性小鼠胰腺癌模型〜3中的CTC,并将CTC进行单分子RNA测序4,从而确定Wnt2是富含CTC的候选基因。 WNT2在胰腺癌细胞中的表达抑制了无神经症,增强了不依赖锚定的球体的形成,并增加了体内转移的倾向。这种作用与纤连蛋白的上调相关,并通过抑制MAP3K7(也称为TAK1)激酶而被抑制。在人类中,胰腺癌细胞形成的非粘附性肿瘤球与多个WNT基因的上调相关,而胰腺CTC在11个病例中有5个显示WNT信号的富集。因此,CTC的分子分析可以确定候选治疗靶标,以防止癌症向远端扩散。

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  • 来源
    《Nature》 |2012年第7408期|p.510-513|共4页
  • 作者单位

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA,Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Helicos BioSciences Corporation, One Kendall Square, Cambridge, Massachusetts 02139, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Helicos BioSciences Corporation, One Kendall Square, Cambridge, Massachusetts 02139, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA;

    Massachusetts General Hospital Cancer Center, Center for Engineering in Medicine, and Departments of Medicine and Surgery, Harvard Medical School, Boston, Massachusetts 02114, USA,Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;

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