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宫颈细胞外基质水凝胶优化宫颈鳞状细胞癌细胞类器官的肿瘤异质性。

Cervical extracellular matrix hydrogel optimizes tumor heterogeneity of cervical squamous cell carcinoma organoids.

机构信息

Department of Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.

The First Affiliated Hospital, Jinan University, Guangzhou 510280, China.

出版信息

Sci Adv. 2024 May 17;10(20):eadl3511. doi: 10.1126/sciadv.adl3511. Epub 2024 May 15.

DOI:10.1126/sciadv.adl3511
PMID:38748808
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11095500/
Abstract

Cervical cancer, primarily squamous cell carcinoma, is the most prevalent gynecologic malignancy. Organoids can mimic tumor development in vitro, but current Matrigel inaccurately replicates the tissue-specific microenvironment. This limitation compromises the accurate representation of tumor heterogeneity. We collected para-cancerous cervical tissues from patients diagnosed with cervical squamous cell carcinoma (CSCC) and prepared uterine cervix extracellular matrix (UCEM) hydrogels. Proteomic analysis of UCEM identified several tissue-specific signaling pathways including human papillomavirus, phosphatidylinositol 3-kinase-AKT, and extracellular matrix receptor. Secreted proteins like FLNA, MYH9, HSPA8, and EEF1A1 were present, indicating UCEM successfully maintained cervical proteins. UCEM provided a tailored microenvironment for CSCC organoids, enabling formation and growth while preserving tumorigenic potential. RNA sequencing showed UCEM-organoids exhibited greater similarity to native CSCC and reflected tumor heterogeneity by exhibiting CSCC-associated signaling pathways including virus protein-cytokine, nuclear factor κB, tumor necrosis factor, and oncogenes EGR1, FPR1, and IFI6. Moreover, UCEM-organoids developed chemotherapy resistance. Our research provides insights into advanced organoid technology through native matrix hydrogels.

摘要

宫颈癌主要是鳞状细胞癌，是最常见的妇科恶性肿瘤。类器官可以在体外模拟肿瘤的发展，但目前的 Matrigel 并不能准确复制组织特异性的微环境。这种局限性限制了对肿瘤异质性的准确描述。我们从诊断为宫颈鳞状细胞癌 (CSCC) 的患者中收集了癌旁宫颈组织，并制备了子宫颈细胞外基质 (UCEM) 水凝胶。UCEM 的蛋白质组分析确定了几个组织特异性信号通路，包括人乳头瘤病毒、磷脂酰肌醇 3-激酶-AKT 和细胞外基质受体。存在 FLNA、MYH9、HSPA8 和 EEF1A1 等分泌蛋白，表明 UCEM 成功地维持了宫颈蛋白。UCEM 为 CSCC 类器官提供了定制的微环境，使其能够形成和生长，同时保持致瘤潜能。RNA 测序显示，UCEM-类器官与原代 CSCC 更为相似，并通过表现出与 CSCC 相关的信号通路，包括病毒蛋白细胞因子、核因子 κB、肿瘤坏死因子以及癌基因 EGR1、FPR1 和 IFI6，反映了肿瘤的异质性。此外，UCEM-类器官产生了化疗耐药性。我们的研究通过天然基质水凝胶为先进的类器官技术提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e654/11095500/b01232cd37c1/sciadv.adl3511-f8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e654/11095500/cd32156a3e1b/sciadv.adl3511-f1.jpg
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