Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC); and.
Blood. 2017 Jul 27;130(4):501-513. doi: 10.1182/blood-2017-04-776740. Epub 2017 May 22.
SOX11 overexpression in mantle cell lymphoma (MCL) has been associated with more aggressive behavior and worse outcome. However, SOX11 oncogenic pathways driving MCL tumor progression are poorly understood. Here, we demonstrate that SOX11 binds to regulatory regions of 2 important genes for microenvironment signals in cancer: (C-X-C motif) chemokine receptor 4 () and (encoding for focal adhesion kinase [FAK]). Moreover, SOX11 xenograft and human primary MCL tumors overexpress cell migration and stromal stimulation gene signatures compared with their SOX11 counterparts. We show that SOX11 directly upregulates CXCR4 and FAK expression, activating PI3K/AKT and ERK1/2 FAK-downstream pathways in MCL. Concordantly, SOX11 MCL cells have higher cell migration, transmigration through endothelial cells, adhesion to stromal cells, and cell proliferation and display an increased resistance to conventional drug therapies compared with SOX11 MCL cells. Specific FAK inhibition blocks downstream PI3K/AKT- and ERK1/2-mediated phosphorylation. Additionally, specific FAK and PI3K inhibitors reduce SOX11-enhanced MCL cell migration and stromal interactions and revert cell adhesion-mediated drug resistance (CAM-DR) to the same levels as SOX11 MCL cells. In intravenous MCL xenograft models, SOX11 MCL cells display higher cell migration, invasion, and growth compared with SOX11-knockdown cells, and specific FAK and CXCR4 inhibitors impair SOX11-enhanced MCL engraftment in bone marrow. Overall, our results suggest that SOX11 promotes MCL homing and invasion and increases CAM-DR through the direct regulation of CXCR4 and FAK expression and FAK/PI3K/AKT pathway activation, contributing to a more aggressive phenotype. Inhibition of this pathway may represent an efficient strategy to overcome stromal-mediated chemotherapy refractoriness in aggressive MCL.
SOX11 在套细胞淋巴瘤 (MCL) 中的过表达与侵袭性行为增加和预后不良有关。然而，驱动 MCL 肿瘤进展的 SOX11 致癌途径仍知之甚少。在这里，我们证明 SOX11 与癌症中 2 个重要的微环境信号调节区域结合：（C-X-C 基序）趋化因子受体 4 () 和 （编码黏着斑激酶 [FAK]）。此外，与 SOX11 对应的 SOX11 异种移植和人原发性 MCL 肿瘤过表达细胞迁移和基质刺激基因特征。我们表明，SOX11 直接上调 CXCR4 和 FAK 的表达，在 MCL 中激活 PI3K/AKT 和 ERK1/2 FAK 下游途径。一致地，与 SOX11 MCL 细胞相比，SOX11 MCL 细胞具有更高的细胞迁移、穿过内皮细胞的迁移、与基质细胞的黏附以及细胞增殖能力，并且对传统药物治疗具有更高的耐药性。特异性 FAK 抑制阻断下游 PI3K/AKT 和 ERK1/2 介导的磷酸化。此外，特异性 FAK 和 PI3K 抑制剂减少了 SOX11 增强的 MCL 细胞迁移和基质相互作用，并使细胞黏附介导的药物耐药性（CAM-DR）恢复到与 SOX11 MCL 细胞相同的水平。在静脉内 MCL 异种移植模型中，与 SOX11 敲低细胞相比，SOX11 MCL 细胞显示出更高的细胞迁移、侵袭和生长能力，并且特异性 FAK 和 CXCR4 抑制剂会损害 SOX11 增强的 MCL 骨髓定植。总体而言，我们的结果表明 SOX11 通过直接调节 CXCR4 和 FAK 的表达以及 FAK/PI3K/AKT 途径的激活，促进 MCL 的归巢和侵袭，并增加 CAM-DR，从而导致更具侵袭性的表型。抑制该途径可能代表克服侵袭性 MCL 中基质介导的化疗耐药性的有效策略。
