A lack of biological markers has limited our ability to identify the invasive cells responsible for glioblastoma multiforme (GBM). To become migratory and invasive, cells must downregulate matrix adhesions, which could be a physical marker of invasive potential. We engineered murine astrocytes with common GBM mutations, e.g. Ink4a (Ink) or PTEN deletion and expressing a constitutively active EGF receptor truncation (EGFRvIII), to elucidate their effect on adhesion. While loss of Ink or PTEN did not affect adhesion, counterparts expressing EGFRvIII were significantly less adhesive. EGFRvIII reduced focal adhesion size and number, and these cells – with more labile adhesions – displayed enhanced migration. Regulation appears to depend not on physical receptor association to integrins but, rather, on the activity of the receptor kinase, resulting in transcriptional integrin repression. Interestingly, EGFRvIII intrinsic signals can be propagated by cytokine crosstalk to cells expressing wild-type EGFR, resulting in reduced adhesion and enhanced migration. These data identify potential intrinsic and extrinsic mechanisms that gliomas use to invade surrounding parenchyma.

生物标志物的缺乏限制了我们识别导致多形性胶质母细胞瘤 (GBM) 的侵袭性细胞的能力。为了具有迁移性和侵袭性，细胞必须下调基质粘附，这可能是侵袭潜力的物理标志。我们对小鼠星形胶质细胞进行了改造，使其具有常见的 GBM 突变，例如Ink4a ( Ink ) 或PTEN缺失，并表达组成型活性 EGF 受体截短 (EGFRvIII)，以阐明它们对粘附的影响。虽然Ink或PTEN的损失不会影响粘附力，但表达 EGFRvIII 的对应物的粘附力明显较低。 EGFRvIII 减少了粘着斑的大小和数量，并且这些具有更不稳定粘连的细胞显示出增强的迁移。调节似乎不依赖于与整合素的物理受体关联，而是依赖于受体激酶的活性，从而导致转录整合素抑制。有趣的是，EGFRvIII 内在信号可以通过细胞因子串扰传播到表达野生型 EGFR 的细胞，从而导致粘附减少和迁移增强。这些数据确定了神经胶质瘤用来侵入周围实质的潜在内在和外在机制。