PDF(Pubmed)
Abstract：
This study sought to identify β-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRβ), affect these targets to alter natural history or treatment response in patients.
In vitro experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.
CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.
The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.
In vitro experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.
CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.
The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.
摘要：
目的：本研究旨在确定调节硬纤维瘤形成的β-catenin靶标，并确定是否存在外部信号通路，特别是那些被索拉非尼抑制的(例如，PDGFRβ），影响这些目标，以改变患者的自然史或治疗反应。
方法：体外实验利用原代硬纤维组织细胞系来检测β-连环蛋白靶标的调节。使用Alliance试验A091105相关活检在体内评估结果的相关性。
结果：CTNNB1敲低抑制了体外缺氧调节基因的表达，并降低了HIF1α蛋白的水平。ChIP-seq将ABL1鉴定为β-连环蛋白转录靶标，可调节HIF1α和胶质细胞增殖。CTNNB1或HIF1的断代抑制内皮细胞共培养物中桥状细胞诱导的VEGFR2磷酸化和管形成。索拉非尼直接抑制该活性,但也降低了HIF1α蛋白表达和c-Abl活性,同时抑制了类胶质细胞中的PDGFRβ信号传导。相反，PDGF-BB正向调节c-Abl活性和纤维状细胞增殖。在用索拉非尼治疗后的患者的活检样品中通常观察到PDGFRβ和c-Abl磷酸化的减少;基线样品中PDGFRβ/c-Abl途径激活的标志物与安慰剂组患者的肿瘤进展和接受治疗的患者对索拉非尼的反应相关。
结论：β-catenin转录靶ABL1是HIF1α在类胶质细胞中增殖和维持所必需的。通过PDGF信号传导和靶向治疗调节c-Abl活性，从而暗示了肿瘤之间可变的生物学行为的原因，索拉非尼在desmoids中活性的机制，和预测患者预后的标志物。
方法：体外实验利用原代硬纤维组织细胞系来检测β-连环蛋白靶标的调节。使用Alliance试验A091105相关活检在体内评估结果的相关性。
结果：CTNNB1敲低抑制了体外缺氧调节基因的表达，并降低了HIF1α蛋白的水平。ChIP-seq将ABL1鉴定为β-连环蛋白转录靶标，可调节HIF1α和胶质细胞增殖。CTNNB1或HIF1的断代抑制内皮细胞共培养物中桥状细胞诱导的VEGFR2磷酸化和管形成。索拉非尼直接抑制该活性,但也降低了HIF1α蛋白表达和c-Abl活性,同时抑制了类胶质细胞中的PDGFRβ信号传导。相反，PDGF-BB正向调节c-Abl活性和纤维状细胞增殖。在用索拉非尼治疗后的患者的活检样品中通常观察到PDGFRβ和c-Abl磷酸化的减少;基线样品中PDGFRβ/c-Abl途径激活的标志物与安慰剂组患者的肿瘤进展和接受治疗的患者对索拉非尼的反应相关。
结论：β-catenin转录靶ABL1是HIF1α在类胶质细胞中增殖和维持所必需的。通过PDGF信号传导和靶向治疗调节c-Abl活性，从而暗示了肿瘤之间可变的生物学行为的原因，索拉非尼在desmoids中活性的机制，和预测患者预后的标志物。
