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更新于：2025-05-07

TREK1

更新于：2025-05-07

基本信息

别名

K2p2.1、KCNK2、Outward rectifying potassium channel protein TREK-1

+ [10]

简介

K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization. Voltage sensing is coupled to K(+) electrochemical gradient in an 'ion flux gating' mode where outward but not inward ion flow opens the gate. Converts to voltage-independent 'leak' conductance mode upon stimulation by various stimuli including mechanical membrane stretch, acidic pH, heat and lipids. Reversibly converts between a voltage-insensitive K(+) 'leak' channel and a voltage-dependent outward rectifying K(+) channel in a phosphorylation-dependent manner (By similarity) (PubMed:10321245, PubMed:10784345, PubMed:11319556, PubMed:23169818, PubMed:30573346, PubMed:38605031). Homo- and heterodimerizes to form functional channels with distinct regulatory and gating properties (By similarity). In trigeminal ganglia sensory neurons, the heterodimer of KCNK2/TREK-1 and KCNK18/TRESK inhibits neuronal firing and neurogenic inflammation by stabilizing the resting membrane potential at K(+) equilibrium potential as well as by regulating the threshold of action potentials and the spike frequency (By similarity). At trigeminal A-beta afferent nerves, the heterodimer of KCNK2/TREK-1 and KCNK4/TRAAK is mostly coexpressed at nodes of Ranvier where it conducts voltage-independent mechanosensitive and thermosensitive currents, allowing rapid action potential repolarization, high speed and high frequence saltatory conduction on myelinated nerves to ensure prompt sensory responses (By similarity). In hippocampal astrocytes, the heterodimer of KCNK2/TREK-1 and KCNK1/TWIK-1 allows passive K(+) conductance under basal conditions, but changes ion selectivity and becomes permeable to L-glutamate and Cl(-) ions upon binding to G-protein subunit GNG4 in stimulated astrocytes. Mediates rapid L-glutamate release in response to activation of G-protein-coupled receptors, such as F2R and CNR1 (By similarity). In hippocampal pyramidal neurons, the homodimer of KCNK2/TREK-1 contributes to gamma-aminobutyric acid (GABA) B-induced slow inhibitory postsynaptic potential. Associates with AKAP5 and Gs-protein-coupled receptor B2AR at postsynaptic dense bodies and converts to a leak channel no longer sensitive to stimulation by arachidonic acid, acidic pH or mechanical stress, nor inhibited by Gq-coupled receptors but still under the negative control of Gs-coupled receptors (By similarity). Permeable to other monovalent cations such as Rb(+) and Cs(+) (By similarity). Does not display channel activity but reduces the channel activity of isoform 1 and isoform 2 and reduces cell surface expression of isoform 2.

关联

项与 TREK1 相关的药物

BL-1249

靶点

TREK1

作用机制

TREK1刺激剂

在研机构

Bristol Myers Squibb Co.

原研机构

Bristol Myers Squibb Co.

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

ONO-2920632

靶点

TREK1 x TREK2

作用机制

TREK1刺激剂 [+1]

在研机构

Ono Pharmaceutical Co., Ltd. [+1]

原研机构

Ono Pharmaceutical Co., Ltd. [+1]

在研适应症

疼痛

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

NCC-0768

靶点

TREK1

作用机制

TREK1刺激剂

在研机构

Nissan Chemical Corp.

原研机构

Nissan Chemical Corp.

在研适应症

疼痛

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TREK1 相关的临床结果

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100 项与 TREK1 相关的转化医学

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0 项与 TREK1 相关的专利（医药）

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714

项与 TREK1 相关的文献（医药）

2025-04-01·Glia

Astrocytic NHERF‐1 Increases Seizure Susceptibility by Inhibiting Surface Expression of TREK‐1

Article

作者: Lee, Soomin ; Kim, Seong‐Seop ; Kim, Ajung ; Park, Sunyoung ; Ryoo, Kanghyun ; Lee, Shinae ; Yi, Gwan‐Su ; Bae, Yeonju ; Noh, Junyeol ; Park, Jae‐Yong ; Hwang, Eun Mi

ABSTRACTMature hippocampal astrocytes exhibit a linear current‐to‐voltage (I‐V) K+ membrane conductance called passive conductance. It is estimated to enable astrocytes to keep potassium homeostasis in the brain. We previously reported that the TWIK‐1/TREK‐1 heterodimeric channels are crucial for astrocytic passive conductance. However, the regulatory mechanism of these channels by other binding proteins remains elusive. Here, we identified Na+/H+ exchange regulator‐1 (NHERF‐1), a protein highly expressed in astrocytes, as a novel interaction partner for these channels. NHERF‐1 endogenously bound to TWIK‐1/TREK‐1 in hippocampal cultured astrocytes. When NHERF‐1 is overexpressed or silenced, surface expression and activity of TWIK‐1/TREK‐1 heterodimeric channels are inhibited or enhanced, respectively. Furthermore, we confirmed that reduced astrocytic passive conductance by NHERF‐1 overexpressing in the hippocampus increases kainic acid (KA)‐induced seizure sensitivity. Taken together, these results suggest that NHERF‐1 is a key regulator of TWIK‐1/TREK‐1 heterodimeric channels in astrocytes and suppression of TREK‐1 surface expression by NHERF‐1 increases KA‐induced seizure susceptibility via reduction of astrocytic passive conductance.

2025-03-13·Journal of Medicinal Chemistry

Discovery of Isobenzofuran-1(3H)-one Derivatives as Selective TREK-1 Inhibitors with In Vitro and In Vivo Neuroprotective Effects

Article

作者: Cen, Yao ; Zhang, Fan ; Wang, Chengyan ; Xie, Yiming ; Zheng, Xiaotong ; Wei, Ziyi ; Zhou, Jie ; Wang, Xiaoyu ; Liu, Kaiyue ; Xu, Bailing ; Ji, Yunyun

TREK-1 regulates neuronal excitability and neuronal cell apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure-activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC₅₀ values of a low micromolar level. Among them, Cpd8l potently and selectively inhibited TREK-1 (IC₅₀ = 0.81 μM, selectivity >30 fold over other K⁺, Na⁺, and TRP channels). Cpd8l remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, Cpd8l could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that Cpd8l may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.

2025-03-05·ACS Chemical Neuroscience

Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator In Vivo Tool Compound

Article

作者: Mori, Takahiro ; Sekioka, Yoko ; Lindsley, Craig W. ; Denton, Jerod S. ; Boutaud, Olivier ; Kurata, Haruto ; Yashiro, Kentaro ; Engers, Darren W. ; Isami, Koichi ; McGowan, Kevin M. ; Kokubo, Masaya ; Bridges, Thomas M. ; Kato, Junya ; Iwaki, Yuzo ; Wieting, Joshua ; Urata, Hirohito

Herein we describe our initial work on the K₂P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = 19b) emerged as a reasonably potent (human Tl⁺; TREK-1 EC₅₀ = 2.8 μM (95% E_max), TREK-2 EC₅₀ = 0.30 μM (184% E_max)), first-generation CNS penetrant (rat K_p = 0.37) in vivo tool compound with selectivity versus the other K₂P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of in vivo tool compounds for the community.

项与 TREK1 相关的新闻（医药）

2025-02-27

·PRNewswire

The debate on MSCs is over; it's time to promote MSC therapy in practice

TIANJIN, China, Feb. 26, 2025 /PRNewswire/ -- The debate on MSCs, mesenchymal stromal cells versus mesenchymal stem cells, continued for more than two decades (since 2006), being the major obstacle for MSCs study and clinical application. The major issue focuses on mesenchymal stem cells could not be approved for clinical application without a thorough test for safety issue (e.g. tumor formation), but all pre-clinical studies proved the MSCs currently prepared and used are safe without the concerns relevant to stem cells, so that they are mesenchymal stromal cells, not stem cells. However, where is the approval? Continue Reading (PRNewsfoto/Tasly) A recent publication in HELIYON ends the debate. The work presented by Regenerative Medicine Research Center at West China Hospital and Tasly Stem cell Biology Laboratory, " Unveiling Distinctions Between Mesenchymal Stromal Cells and Stem Cells by Single-Cell Transcriptomic Analysis " breaks the momentum of confusion in the development of MSC therapy both fundamentally and practically. Using advanced single-cell RNA sequencing (scRNA-seq) and pseudotime trajectory analysis, the research group identified that stem cells exhibit robust self-renewal and differentiation capabilities, mesenchymal stromal cells (MSCs) lack the expression of these critical stemness genes. These genes include SOX2, NANOG, POU5F1, SFRP2, DPPA4, SALL4, ZFP42 and MYCN. On the other hand, there are five critical stromal cell functional genes, TMEM119, FBLN5, KCNK2, CLDN11 and DKK1, that are only expressed in the mesenchymal stromal cells, not in stem cells. The study identified that currently widely used MSCs from different tissues are mesenchymal stromal cells. But, these cells (MSCs) have been long misused as stem cells in many cases. Although the safety issue becomes ignored due to the nature of MSCs, the therapeutic efficacy of these cells has been a big drawback due to the confusion of their mechanism of action. The mechanism of action of stem cells is mediated by their capacity of differentiation to replace the damaged functional cells, but that of stromal cells is medicated by homing and excrete function leading to microenvironmental rejuvenation. Of course, these two different types of cells must be used differently for their differential function in the host. Therefore, this new breakthrough not only ends the debate on MSCs, but also and importantly, helps reorientating our effort towards effective application of MSCs in clinical practice. SOURCE Tasly WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

细胞疗法

2025-02-27

·美通社

MSCs身份尘埃落定：开启间充质基质细胞疗法新时代

天津 2025年2月27日 /美通社/ -- 围绕间充质基质细胞（mesenchymal stromal cells）与间充质干细胞（mesenchymal stem cells）的争议已持续二十余年，成为制约MSCs研究与临床应用的主要障碍。核心问题在于：未经全面安全性验证的间充质干细胞不应获得临床应用批准。然而，所有临床前研究均表明，目前使用的MSCs在安全性上不存在干细胞相关风险，因此应将其准确定义为"间充质基质细胞"而非"干细胞"。针对这一问题，华西医院再生医学研究中心与天士力干细胞生物学实验室联合发表" Unveiling Distinctions Between Mesenchymal Stromal Cells and Stem Cells by Single-Cell Transcriptomic Analysis "研究文章，提供了具有突破性的理论依据，彻底解决了这一长期困扰行业发展的难题。研究团队通过单细胞RNA测序和拟时间轨迹分析技术，首次明确了间充质基质细胞与干细胞的本质区别。研究结果表明，干细胞具有强大的自我更新和分化能力，而间充质基质细胞完全缺乏 SOX2 、 NANOG 、 POU5F1 、 SFRP2 、 DPPA4 、 SALL4 、 ZFP42 及 MYCN 等关键干细胞特性基因的表达。此外，研究首次鉴定出 TMEM119 、 FBLN5 、 KCNK2 、 CLDN11 与 DKK1 等五个基质细胞功能的重要特异性基因，从细胞功能的层面进一步揭示了两者的本质区别。这一研究为MSCs的科学定义和临床应用提供了坚实的理论依据，将推动MSCs疗法迈向实质性突破。拟时间轨迹分析显示，间充质基质细胞在细胞谱系发育上与干细胞存在显著差异这一研究成果不仅终结了MSCs身份的长期争议，更为MSCs临床应用路径的重新规划提供了坚实的科学依据。研究明确区分了两种细胞的作用机制：干细胞依靠分化替代受损细胞，而基质细胞则通过归巢和分泌重塑微环境。这一突破性发现彻底纠正了长期以来对MSCs安全性与有效性的误解，确立了间充质基质细胞的身份鉴定标准，为个性化治疗开辟了新途径。随着这一发现的推广，MSCs疗法将在临床实践中得到更广泛且有效的应用，毫无疑问地推动其在疾病治疗中迎来革命性突破。

细胞疗法临床1期

2024-11-25

·转化医学网

【Science子刊】湘雅医院陈翔团队创新：声学虚拟3D支架，助力肿瘤免疫细胞直接共培养系统

2024年11月22日，中南大学湘雅医院皮肤科陈翔教授团队在期刊《Science Advances》上发表了题为“Acoustic virtual 3D scaffold for direct-interacting tumor organoid–immune cell coculture systems”的研究论文。团队利用AV-Scaf建立了无支架的黑色素瘤和乳腺癌器官组织，并将黑色素瘤器官组织与T细胞进行了共培养。AV-Scaf为肿瘤类器官-免疫细胞研究提供了一种有效的方法，推动了癌症研究和免疫疗法的开发。 2024年11月22日，中南大学湘雅医院皮肤科陈翔教授团队在期刊《Science Advances》上发表了题为“Acoustic virtual 3D scaffold for direct-interacting tumor organoid–immune cell coculture systems”的研究论文。团队利用AV-Scaf建立了无支架的黑色素瘤和乳腺癌器官组织，并将黑色素瘤器官组织与T细胞进行了共培养。AV-Scaf为肿瘤类器官-免疫细胞研究提供了一种有效的方法，推动了癌症研究和免疫疗法的开发。 https://www.science.org/doi/10.1126/sciadv.adr4831 https://www.science.org/doi/10.1126/sciadv.adr4831 关于AV-Scaf 关于AV-Scaf 01 01 三维（3D）细胞培养极大地推动了生命科学和组织工程领域的发展。共培养系统中T细胞的活化，在模拟和研究肿瘤微环境中的免疫反应方面起着关键作用。活化的T细胞可以识别并攻击肿瘤细胞，从而在体外模拟肿瘤的天然免疫反应。然而，传统的类器官培养方法，包括Matrigel、液滴和微室，虽然提供了三维结构支持，但却限制了肿瘤细胞与共培养细胞的直接相互作用，阻碍了共培养系统的T细胞活化效率。三维（3D）细胞培养极大地推动了生命科学和组织工程领域的发展。共培养系统中T细胞的活化，在模拟和研究肿瘤微环境中的免疫反应方面起着关键作用。活化的T细胞可以识别并攻击肿瘤细胞，从而在体外模拟肿瘤的天然免疫反应。然而，传统的类器官培养方法，包括Matrigel、液滴和微室，虽然提供了三维结构支持，但却限制了肿瘤细胞与共培养细胞的直接相互作用，阻碍了共培养系统的T细胞活化效率。在这项研究中，团队开发了一种声学虚拟三维支架（AV-Scaf）方法来实现三维肿瘤类器官培养，从而实现了肿瘤类器官-免疫细胞直接相互作用的共培养系统。与基于Matrigel的方法相比，AV-Scaf直接相互作用共培养系统中的T细胞，表现出高度活化状态，其特点是颗粒酶B（GZMB）（2.82%至17.5%）和干扰素-γ（IFN-γ）（1.36%至16%）显著上调。AV-Scaf实现了肿瘤类器官-免疫细胞直接相互作用的共培养系统，为药物开发和精准个性化治疗，提供了更有效的肿瘤免疫微环境。在这项研究中，团队开发了一种声学虚拟三维支架（AV-Scaf）方法来实现三维肿瘤类器官培养，从而实现了肿瘤类器官-免疫细胞直接相互作用的共培养系统。与基于Matrigel的方法相比，AV-Scaf直接相互作用共培养系统中的T细胞，表现出高度活化状态，其特点是颗粒酶B（GZMB）（2.82%至17.5%）和干扰素-γ（IFN-γ）（1.36%至16%）显著上调。 AV-Scaf实现了肿瘤类器官-免疫细胞直接相互作用的共培养系统，为药物开发和精准个性化治疗，提供了更有效的肿瘤免疫微环境。用于无支架肿瘤细胞器的AV-Scaf 用于无支架肿瘤细胞器的AV-Scaf 02 02 AV-Scaf包括通过US换能器和透镜产生聚焦声漩涡，这种配置旨在实现肿瘤细胞在焦平面内的聚集。设计的漩涡聚焦声场能在最佳位置聚集肿瘤细胞，并将它们聚合成适当大小的细胞簇，同时还能施加非接触式机械刺激。这促进了细胞间的交流，并在不降低细胞活力的情况下，诱导细胞进一步自组织成有机体。声波辐射力和流媒体可用于在不直接接触的情况下，将肿瘤细胞操纵成团。除了细胞生物组装，US还能通过激活离子通道的机械刺激触发细胞重编程。例如，US可以激活不同的离子通道，包括TRP、TREK、TRAAK和PIEZO系列，从而改变细胞的行为。US可显著增强钙离子的流入，从而加速基于细胞组装的细胞间相互作用过程。团队将聚焦涡旋声场用作虚拟三维支架，以加速肿瘤细胞的自组织。由于不含基质，AV-Scaf获得的三维肿瘤类器官模型是在二维环境中形成的。因此，团队无支架肿瘤类器官模型具有很强的可扩展性，更容易建立能准确代表肿瘤微环境的共培养系统。 AV-Scaf包括通过US换能器和透镜产生聚焦声漩涡，这种配置旨在实现肿瘤细胞在焦平面内的聚集。设计的漩涡聚焦声场能在最佳位置聚集肿瘤细胞，并将它们聚合成适当大小的细胞簇，同时还能施加非接触式机械刺激。这促进了细胞间的交流，并在不降低细胞活力的情况下，诱导细胞进一步自组织成有机体。声波辐射力和流媒体可用于在不直接接触的情况下，将肿瘤细胞操纵成团。除了细胞生物组装，US还能通过激活离子通道的机械刺激触发细胞重编程。例如，US可以激活不同的离子通道，包括TRP、TREK、TRAAK和PIEZO系列，从而改变细胞的行为。US可显著增强钙离子的流入，从而加速基于细胞组装的细胞间相互作用过程。团队将聚焦涡旋声场用作虚拟三维支架，以加速肿瘤细胞的自组织。由于不含基质，AV-Scaf获得的三维肿瘤类器官模型是在二维环境中形成的。因此，团队无支架肿瘤类器官模型具有很强的可扩展性，更容易建立能准确代表肿瘤微环境的共培养系统。用于无支架肿瘤细胞器的AV-Scaf示意图。用于无支架肿瘤细胞器的AV-Scaf示意图。直接相互作用共培养系统，可提高T细胞活化效率直接相互作用共培养系统，可提高T细胞活化效率 03 03 与Matrigel相比，使用AV-Scaf方法能显著增强T细胞的活化。AV-Scaf组CD45CD8GZMB细胞的百分比，明显高于Matrigel组。同样，CD45CD8IFN-γ细胞在AV-Scaf组也明显多于Matrigel组。这些发现表明，AV-Scaf法有可能在类器官细胞培养系统中为T细胞活化，提供更有效的微环境。AV-Sca方法产生的肿瘤细胞器中没有Matrigel，有利于肿瘤细胞和T细胞直接接触，从而增强T细胞的活化，这对免疫细胞培养药物测试至关重要。这种增强可能会促进T细胞与肿瘤细胞之间更强有力的相互作用，从而有可能提高免疫治疗策略的疗效。与Matrigel相比，使用AV-Scaf方法能显著增强T细胞的活化。AV-Scaf组CD45CD8GZMB细胞的百分比，明显高于Matrigel组。同样，CD45CD8IFN-γ细胞在AV-Scaf组也明显多于Matrigel组。这些发现表明，AV-Scaf法有可能在类器官细胞培养系统中为T细胞活化，提供更有效的微环境。AV-Sca方法产生的肿瘤细胞器中没有Matrigel，有利于肿瘤细胞和T细胞直接接触，从而增强T细胞的活化，这对免疫细胞培养药物测试至关重要。这种增强可能会促进T细胞与肿瘤细胞之间更强有力的相互作用，从而有可能提高免疫治疗策略的疗效。建立和分析由AV-Scaf促进的肿瘤类器官-T细胞共培养系统。建立和分析由AV-Scaf促进的肿瘤类器官-T细胞共培养系统。总结总结 04 04 1. AV-Scaf作为Matrigel替代品的潜力：研究结果表明，AV-Scaf在类器官形成中提供了与Matrigel相似的结果，凸显了其作为替代品的潜力。 1. AV-Scaf作为Matrigel替代品的潜力：研究结果表明，AV-Scaf在类器官形成中提供了与Matrigel相似的结果，凸显了其作为替代品的潜力。 2. 共培养实验与免疫疗法研究的相关性：与T细胞的共培养实验表明，基于AV-Scaf的器官组织能更准确地再现肿瘤微环境，观察到的T细胞活化效率凸显了该模型与免疫疗法研究的相关性。 2. 共培养实验与免疫疗法研究的相关性：与T细胞的共培养实验表明，基于AV-Scaf的器官组织能更准确地再现肿瘤微环境，观察到的T细胞活化效率凸显了该模型与免疫疗法研究的相关性。 3. PD-1抗体的细胞毒性实验：实验强调了共培养模型在免疫疗法应用方面的巨大潜力。 3. PD-1抗体的细胞毒性实验：实验强调了共培养模型在免疫疗法应用方面的巨大潜力。 4. 开发可扩展且与生理相关的类器官培养方法：研究强调了开发这类方法的重要性，AV-Scaf方法规避了传统支架材料的局限性，为生成肿瘤类器官和共培养系统提供了一个强大的多功能平台。 4. 开发可扩展且与生理相关的类器官培养方法：研究强调了开发这类方法的重要性，AV-Scaf方法规避了传统支架材料的局限性，为生成肿瘤类器官和共培养系统提供了一个强大的多功能平台。 5. AV-Scaf方法的可扩展性和简易性：这些特性使其成为高通量筛选和个性化医学应用的一个极具吸引力的选择。 5. AV-Scaf方法的可扩展性和简易性：这些特性使其成为高通量筛选和个性化医学应用的一个极具吸引力的选择。 6. 对组织工程和再生医学领域的潜在影响：AV-Scaf方法为类器官培养提供了一个更可靠、更可扩展的平台，有可能对这些领域产生重大影响，最终改善癌症患者的临床治疗效果。 6. 对组织工程和再生医学领域的潜在影响： AV-Scaf方法为类器官培养提供了一个更可靠、更可扩展的平台，有可能对这些领域产生重大影响，最终改善癌症患者的临床治疗效果。参考资料：参考资料： 1.S. Nath, G. R. Devi, Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol. Ther. 163, 94–108 (2016). 1.S. Nath, G. R. Devi, Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol. Ther. 163, 94–108 (2016). 2.J. Lou, R. Stowers, S. Nam, Y. Xia, O. Chaudhuri, Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture. Biomaterials 154, 213–222 (2018). 2.J. Lou, R. Stowers, S. Nam, Y. Xia, O. Chaudhuri, Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture. Biomaterials 154, 213–222 (2018).