Chen Xue-Yu, Wang Meng-Yuan, Shu Xin, Li Jun, Tang Ruizhi, Liu Xi-Qiu
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Mater Today Bio. 2025 Apr 29;32:101818. doi: 10.1016/j.mtbio.2025.101818. eCollection 2025 Jun.
As multiple malignant phenotypes appear during cancer progression, it is essential to recognize the possible mechanisms from original to metastatic states. However, both two-dimensional monolayer cell culture and in vivo animal models have their inherent limitations, such as lack of proper cell-ECM interactions and uncontrollable variables. By their heterogeneous simulation of tumor processes, 3D organoids can better recapitulate real tumor characteristics and more realistic responses to distinct factors. Herein, this study was designed to establish in vitro 3D breast cancer organoid models in the recreating tumor-stroma niche by using alginate cryogels to mimic the porous ECM, especially to introduce the controlled release of matrix-bound growth factor EGF (83 % positive in human breast cancers). The matrix-bound EGF in the biomimetic ECM promoted malignant phenotypes of breast cancer organoids in proliferation, migration, epithelial-mesenchymal transition, apoptosis and drug resistance, in accordance with clinical evidence. The multi-omics analyses combined with molecular biological experiments revealed both cytokine-cytokine receptor interaction and ECM-receptor interaction functioned to activate PI3K-AKT pathways, to stimulate tumor-promoting cytokines (eg., IL18, IL33, GDF-15), to promote gene expression of ECM components (eg., FN1) and metabolic enzymes (eg., GOT2), and finally to reprogram breast cancer energy metabolism. This system would represent a new paradigm of cancer progression studies using in vitro 3D organoids in a biomimetic ECM, in order to develop novel therapeutic strategies and evaluate preclinical treatments.
由于在癌症进展过程中会出现多种恶性表型，因此有必要认识从原发状态到转移状态的可能机制。然而，二维单层细胞培养和体内动物模型都有其固有的局限性，如缺乏适当的细胞与细胞外基质（ECM）相互作用以及存在不可控变量。通过对肿瘤过程的异质性模拟，三维类器官能够更好地重现真实肿瘤特征以及对不同因素更逼真的反应。在此，本研究旨在通过使用藻酸盐冷冻凝胶模拟多孔ECM来重建肿瘤-基质微环境，从而建立体外三维乳腺癌类器官模型，特别是引入基质结合生长因子表皮生长因子（EGF，在人类乳腺癌中83%呈阳性）的控释。仿生ECM中基质结合的EGF促进了乳腺癌类器官在增殖、迁移、上皮-间质转化、凋亡和耐药性方面的恶性表型，这与临床证据相符。多组学分析结合分子生物学实验表明，细胞因子-细胞因子受体相互作用和ECM-受体相互作用均发挥作用激活PI3K-AKT信号通路，刺激促肿瘤细胞因子（如IL18、IL33、GDF-15），促进ECM成分（如FN1）和代谢酶（如GOT2）的基因表达，最终重编程乳腺癌能量代谢。该系统将代表一种使用体外三维类器官在仿生ECM中进行癌症进展研究的新范式，以开发新的治疗策略并评估临床前治疗。
