SEMA7A-mediated Juxtacrine Stimulation of IGFBP-3 Upregulates IL-17RB at Pancreatic Cancer Invasive Front

Tumor invasion is the hallmark of tumor malignancy. The invasive infiltration pattern of tumor cells located at the leading edge is highly correlated with metastasis and unfavorable patient outcomes. However, the regulatory mechanisms governing tumor malignancy at the invasive margin remain unclear. The IL-17B/IL-17RB pathway is known to promote pancreatic cancer invasion and metastasis, yet the specific mechanisms underlying IL-17RB upregulation during invasion are poorly understood. In this study, we unveiled a multistep process for IL-17RB upregulation at the invasive margin, which occurs through direct communication between tumor cells and fibroblasts. Tumor ATP1A1 facilitates plasma membrane expression of SEMA7A, which binds to and induces IGFBP-3 secretion from fibroblasts. The resulting gradient of IGFBP-3 influences the direction and enhances IL-17RB expression to regulate SNAI2 in invasion. These findings highlight the importance of local tumor-fibroblast interactions in promoting cancer cell invasiveness, potentially leading to the development of new therapeutic strategies targeting this communication.

Original raw data and uncropped Western blots are organized in a separate worksheet for each figure.

肿瘤侵袭是肿瘤恶性的显著特征。位于侵袭前沿的肿瘤细胞的侵袭性浸润模式与转移及患者不良预后高度相关。然而，调控肿瘤侵袭边缘恶性发展的机制尚不明确。已知 IL-17B/IL-17RB 通路可促进胰腺癌侵袭和转移，但侵袭过程中 IL-17RB 上调的具体机制理解甚少。在本研究中，我们揭示了侵袭边缘 IL-17RB 上调的多步骤过程，该过程通过肿瘤细胞与成纤维细胞之间的直接通讯实现。肿瘤 ATP1A1 促进 SEMA7A 在质膜上的表达，SEMA7A 与成纤维细胞结合并诱导 IGFBP-3 的分泌。由此产生的 IGFBP-3 梯度影响方向并增强 IL-17RB 表达，从而调控侵袭过程中的 SNAI2。这些发现突显了局部肿瘤-成纤维细胞相互作用在促进癌细胞侵袭性中的重要性，可能为针对这种通讯的新治疗策略的开发提供启示。

原始数据及未裁剪的 Western blot 图像按照每个图分别组织在单独的工作表中。