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GDF-15 预测上皮样血管内皮细胞瘤的侵袭性，并通过抑制 ATF4/ATF5 被西罗莫司下调。

GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.

机构信息

Medical Oncology Unit 2, Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori, Milan, Italy.

Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

出版信息

Clin Cancer Res. 2024 Nov 15;30(22):5122-5137. doi: 10.1158/1078-0432.CCR-23-3991.

DOI:10.1158/1078-0432.CCR-23-3991
PMID:39283723
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11565171/
Abstract

PURPOSE

Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness.

EXPERIMENTAL DESIGN

A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness.

RESULTS

ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness.

CONCLUSIONS

This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients.

摘要

目的

上皮样血管内皮细胞瘤（EHE）是一种极罕见的肉瘤，由于晚期病例中常规化疗疗效有限，治疗存在挑战，因此需要探索新的治疗途径和鉴定新的侵袭性生物标志物。本研究旨在：（i）利用 EHE 的患者来源异种移植模型及其相关细胞系评估西罗莫司的疗效；（ii）分析两个不同的患者队列，以确定 EHE 侵袭性的循环生物标志物。

实验设计

从一名晚期 EHE 患者中建立了患者来源的异种移植模型和相应的细胞系，在组织形态学、WWTR1::CAMTA1 融合存在以及基因组和转录组谱方面与原始肿瘤具有一致性。利用两个独立的患者系列来研究生长/分化因子 15（GDF-15）血清水平与 EHE 侵袭性之间的关系。

结果

EHE 细胞培养物和携带 EHE 小鼠的血液 ELISA 分析显示 EHE 细胞释放 GDF-15。与多柔比星相比，西罗莫司表现出明显更高的抗肿瘤活性，同时在体内和体外均降低 GDF-15 的表达/释放。这种降低归因于药物诱导的 4E-BP1 磷酸化/激活抑制以及随后的 GDF-15 转录因子 ATF4 和 ATF5 的下调。两个独立的患者系列的血液样本分析表明，GDF-15 与 EHE 的侵袭性之间存在显著相关性。

结论

本研究将 GDF-15 鉴定为 EHE 侵袭性的一种新型生物标志物，并强调了西罗莫司在我们的实验模型中优于多柔比星的疗效。西罗莫司对 GDF-15 释放的抑制作用表明其可能作为监测患者药物活性的生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/d298d5a8d397/ccr-23-3991_f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/8d978554c03c/ccr-23-3991_f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/246460a0322c/ccr-23-3991_f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/cee38fcf7327/ccr-23-3991_f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/10f4e48e5996/ccr-23-3991_f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/d298d5a8d397/ccr-23-3991_f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/8d978554c03c/ccr-23-3991_f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/246460a0322c/ccr-23-3991_f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/cee38fcf7327/ccr-23-3991_f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/10f4e48e5996/ccr-23-3991_f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf4/11565171/d298d5a8d397/ccr-23-3991_f5.jpg

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