PDF(Pubmed)
Abstract：
UNASSIGNED: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance.
UNASSIGNED: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models.
UNASSIGNED: In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice.
UNASSIGNED: This \"outside-in\" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.
UNASSIGNED: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models.
UNASSIGNED: In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice.
UNASSIGNED: This \"outside-in\" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.
摘要：
背景：以铂为基础的化疗方案是卵巢癌（OC）治疗的支柱，但化疗耐药的出现带来了重大的临床挑战.卵巢癌干细胞（OCSCs）在初级治疗结束时的持久性有助于疾病复发。这里,我们假设细胞外基质在化疗期间保护CSC，并通过激活整合素连接激酶（ILK）支持其致瘤功能，耐药的关键酶。方法使用整合的蛋白质组学和基因表达分析研究TCGA数据集和OC模型，并检查ILK与化学耐药途径和临床结局的相关性。典型的Wnt通路成分,促生存信号，使用OC模型检查干性。为了研究ILK在OCSC表型中的作用，在体外和体内OC模型中使用了ILK与卡铂的新型药理学抑制剂。结果响应纤维连接蛋白（FN）分泌增加和整合素β1聚集，异常ILK激活支持OCSC表型，有助于OC球状体增殖并降低对铂治疗的反应。在肿瘤中检测到ILK与Wnt受体卷曲7（Fzd7）形成的复合物，并显示出与转移进展的强相关性。此外，TCGA数据集证实，高级别浆液性卵巢肿瘤中ILK和Fzd7的联合表达与化疗反应降低和患者预后不良相关。机械上,ILK与Fzd7的相互作用增加了对Wnt配体的反应，从而放大干性相关的Wnt/β-连环蛋白信号传导。值得注意的是,临床前研究表明，新的ILK抑制剂化合物22（cpd-22）单独破坏了ILK与Fzd7和CSC增殖的相互作用。此外，当与卡铂合用时，这种破坏导致持续的AKT抑制，OCSCs的凋亡损伤和小鼠致瘤性降低。结论这种“外向内”的信号机制可能是可操作的，ILK-Fzd7的联合靶向可能代表了根除OCSCs和改善患者预后的新治疗策略。
