Suppression of Endothelial Cell FAK Expression Reduces Pancreatic Ductal Adenocarcinoma Metastasis after Gemcitabine Treatment.
Suppression of Endothelial Cell FAK Expression Reduces Pancreatic Ductal Adenocarcinoma Metastasis after Gemcitabine Treatment.
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DOI：
10.1158/0008-5472.can-20-3807
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发表时间：
2022-05-16
期刊：
影响因子：
11.2
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中科院分区：
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这些发现确立了组合内皮细胞FAK靶向与吉西他滨一起在未来临床应用中控制胰腺导管腺癌患者转移的潜在效用。尽管在实体癌的治疗方面取得了实质性进展，但对治疗的耐药性仍然是延长无进展生存期的主要障碍。胰腺导管腺癌（PDAC）是最具侵袭性的癌症之一，具有高水平的肝转移。原发性PDAC是高度缺氧的，并且转移瘤对一线治疗（包括吉西他滨）具有抗性。最近的研究表明，在原发性肿瘤模型中，内皮细胞（EC）粘着斑激酶（FAK）调节DNA损伤治疗诱导的血管分泌因子和化疗敏感性。在这里，我们表明，在原位和自发性PDAC小鼠模型中，EC-FAK的诱导性丢失不足以影响原发性肿瘤的生长，但可以降低肝和肺转移负荷，并提高吉西他滨治疗小鼠的存活率，但不能提高未经治疗的小鼠的存活率。EC-FAK缺失不影响原发性肿瘤血管生成、肿瘤血管渗漏或转移的早期事件，包括循环肿瘤细胞的数量、肿瘤细胞归巢或转移性接种。磷酸化蛋白质组学分析显示，与吉西他滨处理的野生型EC相比，吉西他滨处理的FAK缺失EC中MAPK、RAF和PAK信号通路下调。此外，低水平的EC-FAK与吉西他滨治疗的PDAC患者的生存率增加和复发率降低相关，支持这些发现的临床相关性。总之，我们已经确定了EC-FAK在吉西他滨治疗后调节PDAC转移中的新作用，其影响结果。这些发现确立了组合内皮细胞FAK靶向与吉西他滨一起在未来临床应用中控制胰腺导管腺癌患者转移的潜在效用。
These findings establish the potential utility of combinatorial endothelial cell FAK targeting together with gemcitabine in future clinical applications to control metastasis in patients with pancreatic ductal adenocarcinoma. Despite substantial advances in the treatment of solid cancers, resistance to therapy remains a major obstacle to prolonged progression-free survival. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a high level of liver metastasis. Primary PDAC is highly hypoxic, and metastases are resistant to first-line treatment, including gemcitabine. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy–induced angiocrine factors and chemosensitivity in primary tumor models. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC is not sufficient to affect primary tumor growth but reduces liver and lung metastasis load and improves survival rates in gemcitabine-treated, but not untreated, mice. EC-FAK loss did not affect primary tumor angiogenesis, tumor blood vessel leakage, or early events in metastasis, including the numbers of circulating tumor cells, tumor cell homing, or metastatic seeding. Phosphoproteomics analysis showed a downregulation of the MAPK, RAF, and PAK signaling pathways in gemcitabine-treated FAK-depleted ECs compared with gemcitabine-treated wild-type ECs. Moreover, low levels of EC-FAK correlated with increased survival and reduced relapse in gemcitabine-treated patients with PDAC, supporting the clinical relevance of these findings. Altogether, we have identified a new role of EC-FAK in regulating PDAC metastasis upon gemcitabine treatment that impacts outcome. These findings establish the potential utility of combinatorial endothelial cell FAK targeting together with gemcitabine in future clinical applications to control metastasis in patients with pancreatic ductal adenocarcinoma.