Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer
Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer
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DOI：
10.1158/0008-5472.can-20-4048
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发表时间：
2021-07-15
期刊：
影响因子：
11.2
通讯作者：
Fukunaga, Koichi
中科院分区：
文献类型：
--
作者：
Ishioka, Kota;Yasuda, Hiroyuki;Fukunaga, Koichi
肺腺癌转分化为小细胞肺癌（SCLC）已在携带EGFR突变的肺癌病例亚组中报告。一些研究报道了TP 53和RB 1改变在转分化中的先决作用。然而，转分化的机制仍然研究不足，明确的额外事件，第三次打击，转分化尚未确定。此外，没有前瞻性实验提供转分化的直接证据。在这项研究中，我们表明，FGF 9上调在转分化中起着至关重要的作用。来自转分化SCLC患者的配对肿瘤样品的整合组学分析显示出FGF 9的稳健上调。此外，在6个配对样品中的4个（66.7%）中在蛋白质水平上证实了FGF 9上调。FGF 9诱导通过FGFR途径的细胞自主激活将小鼠肺腺癌衍生细胞在体内转化为SCLC样肿瘤。用泛FGFR抑制剂AZD 4547体内治疗转分化的SCLC样肿瘤抑制生长。此外，在已建立的人肺腺癌细胞中，FGF 9诱导神经内分泌分化，这是SCLC的病理特征。因此，研究结果提供了直接证据FGF 9介导的小细胞肺癌转分化，并提出FGF 9-FGFR轴作为治疗的目标为transdifferentiated SCLC.Significance：这项研究表明，FGF 9在肺腺癌的小细胞肺癌的转分化中发挥作用。
Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC.Significance: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.