Generating in vitro models of NTRK-fusion mesenchymal neoplasia as tools for investigating kinase oncogenic activation and response to targeted therapy.
Generating in vitro models of NTRK-fusion mesenchymal neoplasia as tools for investigating kinase oncogenic activation and response to targeted therapy.
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DOI：
10.1038/s41389-023-00454-6
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发表时间：
2023-02-17
期刊：
影响因子：
6.2
通讯作者：
Antonescu, Cristina R.
中科院分区：
文献类型：
--
作者：
Vanoli, Fabio;Herviou, Laurie;Tsuda, Yusuke;Sung, Patricia;Xie, Ziyu;Fishinevich, Eve;Min, Soe S.;Mallen, William;de Wardin, Henry de Traux;Zhang, Yanming;Jasin, Maria;Antonescu, Cristina R.
神经营养酪氨酸受体激酶（NTRK）基因融合作为泛肿瘤致癌驱动因子的发现，导致了肿瘤学新的个性化治疗。最近对间充质肿瘤中NTRK融合的研究已经确定了几种新兴的软组织肿瘤实体，表现出不同的表型和临床行为。其中，类似脂肪纤维瘤病或恶性周围神经鞘肿瘤的肿瘤常存在染色体内NTRK1重排，而大多数婴儿纤维肉瘤以典型的ETV6::NTRK3融合为特征。然而，适当的细胞模型来研究激酶的致癌活化如何通过基因融合驱动如此广泛的形态和恶性肿瘤的机制是缺乏的。基因组编辑的进步促进了等基因细胞系中染色体易位的有效产生。在这项研究中，我们采用了多种策略来模拟NTRK融合，包括LMNA::NTRK1（间质缺失）和ETV6::NTRK3（互易易位）在人胚胎干（hES）细胞和间充质祖细胞（hES- mp）中的融合。在这里，我们采用各种方法通过诱导DNA双链断裂（DSBs）来模拟非互惠的染色体内缺失/易位，利用同源定向修复（HDR）或非同源末端连接（NHEJ）的修复机制。在hES细胞或hES- mp中表达LMNA::NTRK1或ETV6::NTRK3融合物均不影响细胞增殖。然而，在hES- mp中，融合转录本的mRNA表达水平显著上调，并且LMNA::NTRK1融合癌蛋白仅在hES- mp中被磷酸化，而在hES细胞中未被磷酸化。同样，与神经元和神经外胚层谱系相关的ntrk1驱动的转录谱主要在hES-MP中上调，这支持了适当的细胞背景在模拟癌症相关畸变中的重要性。作为我们体外模型有效性概念的证明，两种TRK抑制剂Entrectinib和larorectinib减少了磷酸化，这两种抑制剂目前用于靶向治疗具有NTRK融合的肿瘤。
The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as pan-tumor oncogenic drivers has led to new personalized therapies in oncology. Recent studies investigating NTRK fusions among mesenchymal neoplasms have identified several emerging soft tissue tumor entities displaying various phenotypes and clinical behaviors. Among them, tumors resembling lipofibromatosis or malignant peripheral nerve sheath tumors often harbor intra-chromosomal NTRK1 rearrangements, while most infantile fibrosarcomas are characterized by canonical ETV6::NTRK3 fusions. However, appropriate cellular models to investigate mechanisms of how kinase oncogenic activation through gene fusions drives such a wide spectrum of morphology and malignancy are lacking. Progress in genome editing has facilitated the efficient generation of chromosomal translocations in isogenic cell lines. In this study we employ various strategies to model NTRK fusions, including LMNA::NTRK1 (interstitial deletion) and ETV6::NTRK3 (reciprocal translocation) in human embryonic stem (hES) cells and mesenchymal progenitors (hES-MP). Here, we undertake various methods to model non-reciprocal, intrachromosomal deletions/translocations by induction of DNA double strand breaks (DSBs) exploiting either the repair mechanisms of homology directed repair (HDR) or non-homologous end joining (NHEJ). Expression of LMNA::NTRK1 or ETV6::NTRK3 fusions in either hES cells or hES-MP did not affect cell proliferation. However, the level of mRNA expression of the fusion transcripts was significantly upregulated in hES-MP, and phosphorylation of the LMNA::NTRK1 fusion oncoprotein was noted only in hES-MP but not in hES cells. Similarly, an NTRK1-driven transcriptional profile related to neuronal and neuroectodermal lineage was upregulated mainly in hES-MP, supporting the importance of appropriate cellular context in modeling cancer relevant aberrations. As proof of concept of the validity of our in vitro models, phosphorylation was depleted by two TRK inhibitors, Entrectinib and Larotrectinib, currently used as targeted therapy for tumors with NTRK fusions.
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DOI：
10.1097/pas.0000000000001055
发表时间：
2018-06
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Chiang S;Cotzia P;Hyman DM;Drilon A;Tap WD;Zhang L;Hechtman JF;Frosina D;Jungbluth AA;Murali R;Park KJ;Soslow RA;Oliva E;Iafrate AJ;Benayed R;Ladanyi M;Antonescu CR
通讯作者：
Antonescu CR
DOI：
10.1016/j.annonc.2020.08.2232
发表时间：
2020-11
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Demetri GD;Antonescu CR;Bjerkehagen B;Bovée JVMG;Boye K;Chacón M;Dei Tos AP;Desai J;Fletcher JA;Gelderblom H;George S;Gronchi A;Haas RL;Hindi N;Hohenberger P;Joensuu H;Jones RL;Judson I;Kang YK;Kawai A;Lazar AJ;Le Cesne A;Maestro R;Maki RG;Martín J;Patel S;Penault-Llorca F;Premanand Raut C;Rutkowski P;Safwat A;Sbaraglia M;Schaefer IM;Shen L;Serrano C;Schöffski P;Stacchiotti S;Sundby Hall K;Tap WD;Thomas DM;Trent J;Valverde C;van der Graaf WTA;von Mehren M;Wagner A;Wardelmann E;Naito Y;Zalcberg J;Blay JY
通讯作者：
Blay JY
DOI：
10.1002/gcc.22846
发表时间：
2020-08
期刊：
Genes, chromosomes & cancer
影响因子：
--
作者：
Antonescu CR
通讯作者：
Antonescu CR
影响因子：
2.5
作者：
Panagopoulos, Ioannis;Gorunova, Ludmila;Heim, Sverre
通讯作者：
Heim, Sverre
影响因子：
7.5
作者：
Kao, Yu-Chien;Sung, Yun-Shao;Antonescu, Cristina R.
通讯作者：
Antonescu, Cristina R.