NOTCH和PTP4A3改变成为胸膜间皮瘤的新型预测性生物标记物和潜在治疗靶点。

IF 4.5 2区 医学 Q1 ONCOLOGY Lung Cancer Pub Date : 2024-11-07 DOI:10.1016/j.lungcan.2024.108024
Mariacarmela Santarpia , Marta Aliprandi , Calogera Claudia Spagnolo , Amir Avan , Rafael Rosell , Paolo Andrea Zucali , Elisa Giovannetti
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引用次数: 0

摘要

背景:以前的研究表明,NOTCH1 和 NOTCH2 对间皮瘤细胞在缺氧条件下的存活有相反的影响。目的:在本研究中,我们评估了NOTCH1、NOTCH2拷贝数改变(CNAs)是否可预测胸膜间皮瘤(PM)患者的预后,以及对该通路的调节是否可靶向CSCs,增强培美曲塞的活性(同样在缺氧条件下):方法:通过对 "发现队列"(26 名接受培美曲塞化疗的患者)石蜡包埋样本进行高分辨率全基因组测序,确定了复发性 CNA。在 "发现队列 "和两个独立的 "验证队列"(培美曲塞治疗过和未治疗过的患者各 45 人和 40 人)中,通过 PCR 基因拷贝数和表达分析验证了预后性 CNA。在缺氧条件下生长的不同亚群 PM 细胞中,通过 siRNA 对新出现的基因进行了功能分析:结果:在50%的进展期患者中观察到NOTCH2的拷贝数增高,在培美曲塞治疗和未治疗的患者群中,NOTCH2的过表达与预后较差有关。相反,PTP4A3的缺失与临床获益相关,而NOTCH2和PTP4A3均过表达的患者预后更差。此外,通过siRNA在体外沉默NOTCH2可减少迁移,增强PM细胞的凋亡,而PTP4A3抑制剂BR-1可克服NOTCH2/PTP4A3高表达的PM细胞对培美曲塞的耐药性:结论:NOTCH2和PTP4A3的改变与培美曲塞治疗的PM患者的临床结果有关。结论:NOTCH2和PTP4A3的改变与培美曲塞治疗的肺癌患者的临床预后有关,抑制NOTCH通路可用于消灭癌细胞干细胞并改善患者的生存。
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NOTCH and PTP4A3 alterations emerge as novel predictive biomarkers and potential therapeutic targets in pleural mesothelioma

Background

Previous studies showed opposite effects of NOTCH1 and NOTCH2 on mesothelioma cell survival under hypoxia. Mechanisms underlying these effects are not still clear and this pathway plays a key role in angiogenesis and cancer stem cells (CSCs) self-renewal processes.

Purpose

In this study we evaluated whether NOTCH1, NOTCH2 copy number alterations (CNAs) might predict prognosis of patients with pleural mesothelioma (PM) and if the modulation of this pathway might target CSCs, potentiating pemetrexed activity, also in hypoxic conditions.

Methods

Recurrent CNAs were determined by high-resolution whole-genome sequencing from paraffin-embedded samples of a “discovery cohort” (26 patients treated with pemetrexed-based chemotherapy). Prognostic CNAs were validated by PCR gene copy-number and expression analyses in the “discovery” and in two independent “validation” cohorts of pemetrexed-treated and untreated patients (N = 45 and N = 40). Functional analyses of emerging genes were performed through siRNA in different subpopulation of PM cells, growing under hypoxia.

Results

A copy number gain of NOTCH2 was observed in 50% of patients with progressive disease and its overexpression correlated with a worse prognosis in both pemetrexed-treated and untreated-patients’ cohorts. Conversely, losses of PTP4A3 correlated with clinical benefit, while patients with overexpression of both NOTCH2 and PTP4A3 had the worse prognosis. Moreover, NOTCH2 silencing through siRNA in vitro reduced migration, enhancing apoptosis of PM cells, while the PTP4A3 inhibitor BR-1 overcame pemetrexed resistance in PM cells characterized by high NOTCH2/PTP4A3 expression.

Conclusions

NOTCH2 and PTP4A3 alterations are associated with clinical outcomes in pemetrexed-treated PM patients. The inhibition of NOTCH pathway may be exploited to eradicate CSCs and improve patients’ survival.
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来源期刊
Lung Cancer
Lung Cancer 医学-呼吸系统
CiteScore
9.40
自引率
3.80%
发文量
407
审稿时长
25 days
期刊介绍: Lung Cancer is an international publication covering the clinical, translational and basic science of malignancies of the lung and chest region.Original research articles, early reports, review articles, editorials and correspondence covering the prevention, epidemiology and etiology, basic biology, pathology, clinical assessment, surgery, chemotherapy, radiotherapy, combined treatment modalities, other treatment modalities and outcomes of lung cancer are welcome.
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