The use of a multi-metric readout screen to identify EHMT2/G9a-inhibition as a modulator of cancer-associated fibroblast activation state

IF 12.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Biomaterials Pub Date : 2024-10-05 DOI:10.1016/j.biomaterials.2024.122879

Nila C. Wu , Rene Quevedo , Michelle Nurse , Kebria Hezaveh , Haijiao Liu , Fumao Sun , Julien Muffat , Yu Sun , Craig A. Simmons , Tracy L. McGaha , Panagiotis Prinos , Cheryl H. Arrowsmith , Laurie Ailles , Elisa D'Arcangelo , Alison P. McGuigan

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引用次数: 0

Abstract

Cancer-associated fibroblasts (CAFs) play a pivotal role in cancer progression, including mediating tumour cell invasion via their pro-invasive secretory profile and ability to remodel the extracellular matrix (ECM). Given that reduced CAF abundance in tumours correlates with improved outcomes in various cancers, we set out to identify epigenetic targets involved in CAF activation in regions of tumour-stromal mixing with the goal of reducing tumour aggressiveness. Using the GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, we performed an image-based, phenotypic screen that enabled us to identify modulators of CAF abundance and the capacity of CAFs to induce tumour cell invasion. We identified EHMT2 (also known as G9a), an enzyme that targets the methylation of histone 3 lysine 9 (H3K9), as a potent modulator of CAF abundance and CAF-mediated tumour cell invasion. Transcriptomic and functional analysis of EHMT2-inhibited CAFs revealed EHMT2 participated in driving CAFs towards a pro-invasive phenotype and mediated CAF hyperproliferation, a feature typically associated with activated fibroblasts in tumours. Our study suggests that EHMT2 regulates CAF state within the tumour microenvironment by impacting CAF activation, as well as by magnifying the pro-invasive effects of these activated CAFs on tumour cell invasion through promoting CAF hyperproliferation.

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利用多指标读数筛选确定 EHMT2/G9a 抑制是癌症相关成纤维细胞活化状态的调节剂

癌症相关成纤维细胞（CAFs）在癌症进展中发挥着关键作用，包括通过其促侵袭性分泌特征和重塑细胞外基质（ECM）的能力介导肿瘤细胞侵袭。鉴于肿瘤中 CAF 丰度的降低与各种癌症预后的改善相关，我们着手在肿瘤-基质混合区域确定参与 CAF 激活的表观遗传学靶点，目的是降低肿瘤的侵袭性。我们利用 GLAnCE（分区环境实时分析凝胶）平台进行了基于图像的表型筛选，从而确定了 CAF 丰度和 CAF 诱导肿瘤细胞侵袭能力的调节因子。我们发现了EHMT2（又称G9a），它是一种靶向组蛋白3赖氨酸9（H3K9）甲基化的酶，是CAF丰度和CAF介导的肿瘤细胞侵袭的有效调节剂。对EHMT2抑制的CAF进行的转录组学和功能分析表明，EHMT2参与驱动CAF形成侵袭性表型，并介导CAF过度增殖，这是肿瘤中活化成纤维细胞的典型特征。我们的研究表明，EHMT2通过影响CAF的活化以及通过促进CAF的过度增殖放大这些活化的CAF对肿瘤细胞侵袭的促侵袭效应来调节肿瘤微环境中的CAF状态。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomaterials 工程技术-材料科学：生物材料

CiteScore

26.00

自引率

2.90%

发文量

565

审稿时长

46 days

期刊介绍： Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.