NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.
Department of Urology, The Fourth Hospital of Harbin Medical University, Heilongjiang Key Laboratory of Scientific Research in Urology, No. 37 Yi-Yuan Street, Nangang District, Heilongjiang Province, Harbin, 150001, China.
Adv Mater. 2022 Oct;34(43):e2203518. doi: 10.1002/adma.202203518. Epub 2022 Sep 20.
Extracellular matrix (ECM) is crucial in various biological functions during tumor progression, including induction of anoikis resistance and cell adhesion-mediated drug resistance (CAM-DR). Fibronectin (FN) is a vital ECM component with direct regulatory effects on ECM-mediated anoikis resistance and CAM-DR, making it an attractive and innovative therapeutic target for depriving ECM in tumor tissue. Herein, an ECM deprivation system (EDS) is developed based on FN targeting self-assembly peptide for constructing nanofibers in the ECM of renal cell carcinoma (RCC), which contributes to: i) targeting and recognizing FN to form nanofibers for long-term retention in ECM, ii) reversing anoikis resistance via arresting the FN signaling pathway, and iii) serving as a drug-loading platform for sensitizing chemotherapy by ameliorating CAM-DR. The results reveal that EDS significantly reverses anoikis resistance of RCC cells by inhibiting the phosphorylation of FAK, a positive regulator of the FN signaling pathway. Meanwhile, EDS serves as a chemotherapy-sensitizer of cancer, exerting significant synergistic effects with doxorubicin (DOX). In vivo validation experiments show that EDS effectively suppresses metastasis and tumor growth with chemotherapy resistance. Collectively, the innovative EDS notably inhibits the tumor-promoting effect of ECM and may provide a novel approach for suppressing ECM and enhancing chemo-drug sensitivity.
细胞外基质 (ECM) 在肿瘤进展过程中的各种生物学功能中至关重要，包括诱导失巢凋亡抵抗和细胞黏附介导的药物耐药性 (CAM-DR)。纤连蛋白 (FN) 是 ECM 的重要组成部分，对 ECM 介导的失巢凋亡抵抗和 CAM-DR 具有直接的调节作用，使其成为剥夺肿瘤组织中 ECM 的有吸引力和创新性的治疗靶点。在此，基于 FN 靶向自组装肽开发了一种细胞外基质剥夺系统 (EDS) ，用于构建肾细胞癌 (RCC) ECM 中的纳米纤维，有助于：i）靶向和识别 FN 以形成纳米纤维，在 ECM 中长时间保留，ii）通过阻断 FN 信号通路来逆转失巢凋亡抵抗，iii）作为药物加载平台，通过改善 CAM-DR 来增敏化疗。结果表明，EDS 通过抑制 FN 信号通路的正向调节剂 FAK 的磷酸化，显著逆转了 RCC 细胞的失巢凋亡抵抗。同时，EDS 作为癌症的化疗增敏剂，与阿霉素 (DOX) 表现出显著的协同作用。体内验证实验表明，EDS 有效地抑制转移和化疗耐药性肿瘤生长。总的来说，创新的 EDS 显著抑制了 ECM 的促肿瘤作用，可能为抑制 ECM 和增强化疗药物敏感性提供了一种新方法。
