Rapid 3D Bioprinting of Glioblastoma Model Mimicking Native Biophysical Heterogeneity.
Rapid 3D Bioprinting of Glioblastoma Model Mimicking Native Biophysical Heterogeneity.
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DOI：
10.1002/smll.202006050
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Tang M;Tiwari SK;Agrawal K;Tan M;Dang J;Tam T;Tian J;Wan X;Schimelman J;You S;Xia Q;Rana TM;Chen S
多形性胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤，其特征是高度细胞和分子异质性、过度血管化和先天耐药性。目前的治疗方案包括手术切除、放疗和以替莫唑胺为主的化疗相结合，但预后较差，平均预期寿命为 15 个月。尽管进行了大量的研究和药物开发工作，但胶质母细胞瘤的治疗进展仍然停滞不前。细胞成分和细胞外基质（ECM）是 GBM 异质性的两个主要来源。了解癌症的遗传基础和开发新疗法的主要障碍之一是缺乏生理相关和患者特异性的 GBM 肿瘤模型。在这里，我们开发了仿生三区域 GBM 模型，包括肿瘤区域、无细胞 ECM 区域和内皮区域，区域硬度对应于 GBM 基质、病理或正常脑实质和脑毛细血管。患者来源的 GBM 细胞、人内皮细胞和透明质酸衍生物用于生成物种匹配且生化相关的微环境。这项体外研究表明，生物物理信号参与各种肿瘤细胞行为和血管生成潜力，并促进 GBM 的不同分子亚型。僵硬的模型富含间充质亚型，表现出肿瘤细胞的弥漫性侵袭，并诱导突出的血管生成和对替莫唑胺的更高耐药性。同时，软模型展示了经典亚型的富集并支持扩张性细胞生长。我们的研究中使用的 3D 生物打印技术能够实现快速、灵活和可重复的具有生物物理异质性的 GBM 建模，未来的研究可以将其用作可调谐系统来询问 GBM 疾病机制和筛选药物化合物。
Glioblastoma multiforme (GBM) is the most lethal primary brain tumor characterized by high cellular and molecular heterogeneity, hyper-vascularization, and innate drug resistance. Current treatment options include a combination of surgical resection, radiotherapy, and chemotherapy primarily with temozolomide, but the prognosis is poor with an average life expectancy of 15 months. Despite significant research and drug development efforts, therapeutic advances to treat glioblastoma remain stagnant. Cellular components and extracellular matrix (ECM) are the two primary sources of heterogeneity in GBM. One of the major roadblocks in understanding the genetic basis of the cancer and developing new therapies is the lack of physiologically relevant and patient-specific GBM tumor models. Here, we develop biomimetic tri-regional GBM models with a tumor region, an acellular ECM region, and an endothelial region – with regional stiffnesses patterned corresponding to the GBM stroma, pathological or normal brain parenchyma, and brain capillaries. Patient-derived GBM cells, human endothelial cells, and hyaluronic acid derivatives are used to generate a species-matched and biochemically relevant microenvironment. This in vitro study demonstrates that biophysical cues are involved in various tumor cell behaviors and angiogenic potentials and promote different molecular subtypes of GBM. The stiff models are enriched in the mesenchymal subtype, exhibit diffuse invasion of tumor cells, and induce protruding angiogenesis and higher drug resistance to temozolomide. Meanwhile, the soft models demonstrate enrichment in the classical subtype and support expansive cell growth. The 3D bioprinting technology utilized in our study enables rapid, flexible, and reproducible GBM modeling with biophysical heterogeneity that can be employed by future studies as a tunable system to interrogate GBM disease mechanisms and screen drug compounds.
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影响因子：
64.5
作者：
Lee SH;Hu W;Matulay JT;Silva MV;Owczarek TB;Kim K;Chua CW;Barlow LJ;Kandoth C;Williams AB;Bergren SK;Pietzak EJ;Anderson CB;Benson MC;Coleman JA;Taylor BS;Abate-Shen C;McKiernan JM;Al-Ahmadie H;Solit DB;Shen MM
通讯作者：
Shen MM
影响因子：
6.1
作者：
Hribar KC;Finlay D;Ma X;Qu X;Ondeck MG;Chung PH;Zanella F;Engler AJ;Sheikh F;Vuori K;Chen SC
通讯作者：
Chen SC
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
14
作者：
Ma X;Yu C;Wang P;Xu W;Wan X;Lai CSE;Liu J;Koroleva-Maharajh A;Chen S
通讯作者：
Chen S
影响因子：
23.9
作者：
Lathia, Justin D.;Heddleston, John M.;Venere, Monica;Rich, Jeremy N.
通讯作者：
Rich, Jeremy N.