We have identified an epidermal cancer stem (ECS) cell population that drives formation of rapidly growing and highly invasive and vascularized tumors. VEGF-A and neuropilin-1 (NRP-1) are highly expressed in ECS cell tumors and VEGF-A/NRP-1 interaction is required for ECS cell survival and tumor vascularization. We now identify a novel signaling cascade that is triggered by VEGF-A/NRP-1. We show that NRP-1 forms a complex with GIPC1 and α6/β4-integrin to activate FAK/Src signaling, which leads to stabilization of a YAP1/∆Np63α to enhance ECS cell survival, invasion, and angiogenesis. Loss of NRP-1, GIPC1, α6/β4-integrins, YAP1, or ∆Np63α reduces these responses. Moreover, restoration of constituently active YAP1 or ∆Np63α in NRP-1 null cells restores the ECS cell phenotype. Tumor xenograft experiments show that NRP-1 knockout ECS cells form small tumors characterized by reduced vascularization as compared to wild-type cells. The NRP-1 knockout tumors display signaling changes consistent with a role for the proposed signaling cascade. These studies suggest that VEGF-A interacts with NRP-1 and GIPC1 to regulate α6/β4-integrin, FAK, Src, PI3K/PDK1, LATS1 signaling to increase YAP1/∆Np63α accumulation to drive ECS cell survival, angiogenesis, and tumor formation.

中文翻译：

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NRP-1 与 GIPC1 和 α6/β4-整合素相互作用以增加 YAP1/ΔNp63α 依赖性表皮癌干细胞的存活。

我们已经确定了一种表皮癌干细胞 (ECS) 细胞群，该细胞群可驱动快速生长、高侵袭性和血管化肿瘤的形成。VEGF-A 和 neuropilin-1 (NRP-1) 在 ECS 细胞肿瘤中高度表达，VEGF-A/NRP-1 相互作用是 ECS 细胞存活和肿瘤血管形成所必需的。我们现在确定了一种由 VEGF-A/NRP-1 触发的新型信号级联。我们表明 NRP-1 与 GIPC1 和 α6/β4-整合素形成复合物以激活 FAK/Src 信号传导，从而导致 YAP1/ΔNp63α 稳定以增强 ECS 细胞存活、侵袭和血管生成。NRP-1、GIPC1、α6/β4-整合素、YAP1 或 ΔNp63α 的缺失会降低这些反应。此外，在 NRP-1 无效细胞中恢复组成活性 YAP1 或 ΔNp63α 可恢复 ECS 细胞表型。肿瘤异种移植实验表明，与野生型细胞相比，NRP-1 敲除 ECS 细胞形成的小肿瘤的特征是血管形成减少。NRP-1 敲除肿瘤显示的信号变化与所提出的信号级联的作用一致。这些研究表明，VEGF-A 与 NRP-1 和 GIPC1 相互作用以调节 α6/β4-整合素、FAK、Src、PI3K/PDK1、LATS1 信号以增加 YAP1/ΔNp63α 积累以驱动 ECS 细胞存活、血管生成和肿瘤形成.