FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.
FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer.
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DOI：
10.15252/emmm.202012010
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发表时间：
2020-11-06
影响因子：
11.1
通讯作者：
Jean C
中科院分区：
文献类型：
--
作者：
Zaghdoudi S;Decaup E;Belhabib I;Samain R;Cassant-Sourdy S;Rochotte J;Brunel A;Schlaepfer D;Cros J;Neuzillet C;Strehaiano M;Alard A;Tomasini R;Rajeeve V;Perraud A;Mathonnet M;Pearce OM;Martineau Y;Pyronnet S;Bousquet C;Jean C
癌症相关成纤维细胞（CAF）被认为是胰腺导管腺癌（PDAC）中最丰富的基质细胞类型，在肿瘤进展和化疗耐药中发挥着关键作用；然而，CAF 的药物靶点尚未确定。在这里，我们报告说，与健康胰腺成纤维细胞中的活性相比，CAF 中的粘着斑激酶 (FAK) 活性（根据 397 酪氨酸磷酸化水平进行评估）显着增加。成纤维细胞 FAK 活性是 PDAC 患者（120 个 PDAC 样本队列）无病生存和总体生存的独立预后标志物。成纤维细胞内 FAK 的基因失活（FAK 激酶死亡，KD）可减少原发性肿瘤内的纤维化和免疫抑制细胞数量，并显着减少肿瘤扩散。 FAK 药理或基因失活可减少成纤维细胞迁移/侵袭，减少 CAF 的细胞外基质 (ECM) 表达和沉积，改变 ECM 轨迹生成并对 M2 巨噬细胞极化和迁移产生负面影响。因此，CAF 内的 FAK 活性似乎是一种独立的 PDAC 预后标志物和肿瘤细胞侵袭的药物驱动因素。鉴于患者预后不良，了解癌症相关成纤维细胞 (CAF) 如何促进 PDAC 进展具有重要意义。这项研究确定了 CAF 诱导的肿瘤细胞转移的可药物关键调节因子和预后因素：蛋白粘着激酶 (FAK)。
Cancer‐associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease‐free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase‐dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion. Understanding how cancer‐associated fibroblasts (CAFs) promote PDAC progression is of major interest given the poor prognosis of patients. This study identifies a druggable key regulator of CAF‐induced tumour cell metastasis and a prognostic factor: the protein Focal Adhesion Kinase (FAK).
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影响因子：
7
作者：
Cutillas, Pedro R.;Vanhaesebroeck, Bart
通讯作者：
Vanhaesebroeck, Bart
影响因子：
2.9
作者：
Arao, S;Masumoto, A;Otsuki, M
通讯作者：
Otsuki, M
影响因子：
7.5
作者：
Fukushima, Noriyoshi;Kikuchi, Yoshinao;Fukayama, Masashi
通讯作者：
Fukayama, Masashi
影响因子：
29.4
作者：
Bachem, MG;Schneider, E;Adler, G
通讯作者：
Adler, G
影响因子：
11.2
作者：
Hwang, Rosa F.;Moore, Todd;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.