MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice.
MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice.
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DOI：
10.1002/1878-0261.13397
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发表时间：
2023-11
影响因子：
6.6
通讯作者：
Kherrouche, Zoulika
中科院分区：
文献类型：
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作者：
Fernandes, Marie;Hoggard, Brynna;Jamme, Philippe;Paget, Sonia;Truong, Marie-Jose;Gregoire, Valerie;Vinchent, Audrey;Descarpentries, Clotilde;Morabito, Angela;Stanislovas, Justas;Farage, Enoir;Meneboo, Jean-Pascal;Sebda, Sheherazade;Bouchekioua-Bouzaghou, Katia;Nollet, Marie;Humez, Sarah;Perera, Timothy;Fromme, Paul;Grumolato, Luca;Figeac, Martin;Copin, Marie-Christine;Tulasne, David;Cortot, Alexis B.;Kermorgant, Stephanie;Kherrouche, Zoulika
关键词：
MET 受体酪氨酸激酶 (METex14) 的外显子跳跃突变在癌症中越来越多地报道，发生在 3-4% 的非小细胞肺癌 (NSCLC) 中。只有 50% 的患者对 MET 酪氨酸激酶抑制剂 (TKI) 治疗有有益反应，因此需要了解 METex14 致癌性和对 TKI 敏感性的机制。之前的临床前模型尚未完全阐明 METex14 是否是驱动突变，以及其在一系列体外功能和体内致癌性是否需要肝细胞生长因子 (HGF)。使用 CRISPR/Cas9，我们在未转化的人肺细胞中开发了 METex14/WT 等基因模型，并报告说 METex14 单一改变足以驱动 MET 依赖的体外贴壁独立生存和运动以及体内肿瘤发生，使肿瘤对 MET-TKI 敏感。然而，我们还表明，人 HGF (hHGF) 是必需的，正如使用人源化 HGF 敲入小鼠品系在体内所证明的那样，并在 METex14 NSCLC 患者样本的肿瘤细胞中进一步检测到。我们的结果还表明，METex14 致癌性并不是我们的细胞模型中逃避降解的结果。因此，我们开发了一个有价值的临床前研究模型，并提出了具有潜在临床意义的结果。使用 CRISPR/Cas9，我们在未转化的人肺细胞中开发了 METex14/WT 等基因模型，因此没有其他致癌改变的混杂影响。 METex14 单一改变就足够了，但需要 HGF 驱动 MET 依赖性持续磷酸化和信号传导、增强细胞运动性、锚定非依赖性存活、人源化 HGF 敲入小鼠中基因表达和体内肿瘤发生的变化，使肿瘤对 MET-TKIs 敏感。
Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3–4% of non–small‐cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET‐tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET‐dependent in vitro anchorage‐independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET‐TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock‐in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells, thus without the confounding effects of other oncogenic alteration. METex14 single alteration was sufficient but required HGF to drive MET‐dependent sustained phosphorylation and signalling, enhanced cell motility, anchorage‐independent survival, changes in gene expression and in vivo tumorigenesis in humanised HGF knock‐in mice, sensitising tumours to MET‐TKIs.
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DOI：
10.1158/1078-0432.ccr-18-0876
发表时间：
2018-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bahcall M;Awad MM;Sholl LM;Wilson FH;Xu M;Wang S;Palakurthi S;Choi J;Ivanova EV;Leonardi GC;Ulrich BC;Paweletz CP;Kirschmeier PT;Watanabe M;Baba H;Nishino M;Nagy RJ;Lanman RB;Capelletti M;Chambers ES;Redig AJ;VanderLaan PA;Costa DB;Imamura Y;Jänne PA
通讯作者：
Jänne PA
影响因子：
82.9
作者：
Drilon A;Clark JW;Weiss J;Ou SI;Camidge DR;Solomon BJ;Otterson GA;Villaruz LC;Riely GJ;Heist RS;Awad MM;Shapiro GI;Satouchi M;Hida T;Hayashi H;Murphy DA;Wang SC;Li S;Usari T;Wilner KD;Paik PK
通讯作者：
Paik PK
影响因子：
5.2
作者：
Kawakami H;Okamoto I;Okamoto W;Tanizaki J;Nakagawa K;Nishio K
通讯作者：
Nishio K
影响因子：
20.4
作者：
Baldacci, Simon;Figeac, Martin;Cortot, Alexis B.
通讯作者：
Cortot, Alexis B.
影响因子：
20.4
作者：
Jamme, Philippe;Fernandes, Marie;Cortot, Alexis B.
通讯作者：
Cortot, Alexis B.