Zhou Dandan, Li Xiaoxiao, Liu Wencun, Zhang Mingjun, Cheng Ying, Xu Zhousong, Gao Jian, Wang Yiyang
Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Geriatric Medicine, Jiulongpo People's Hospital of Chongqing, Chongqing, China.
Front Bioeng Biotechnol. 2025 Mar 14;13:1564543. doi: 10.3389/fbioe.2025.1564543. eCollection 2025.
Liver cancer, a highly aggressive malignancy, continues to present significant challenges in therapeutic management due to its pronounced chemoresistance. This resistance, which undermines the efficacy of conventional chemotherapy and targeted therapies, is driven by multifaceted mechanisms, with increasing emphasis placed on the protective role of the tumor microenvironment (TME). The hepatocellular carcinoma extracellular matrix (ECM), a primary non-cellular component of the TME, has emerged as a critical regulator in cancer progression and drug resistance, particularly in hepatocellular carcinoma cell (HCC). In this study, a hybrid biomimetic hydrogel was engineered by integrating decellularized hepatocellular carcinoma matrix (DHCM) with gelatin methacrylate (GelMA) precursors. This composite DHCM/GelMA hydrogel was designed to replicate the physicochemical and functional properties of the hepatocellular carcinoma ECM, thereby offering a biomimetic platform to explore the interactions between HCCs and their microenvironment. Leveraging a custom-designed microfluidic 3D printing platform, we achieved high-throughput fabrication of HCC-encapsulated DHCM/GelMA microgels, characterized by enhanced uniformity, biocompatibility, and scalability. These microgels facilitated the construction of hepatocellular carcinoma microtissues, which were subsequently employed for chemoresistance studies. Our findings revealed that DHCM/GelMA microgels closely mimic the hepatocellular carcinoma tumor microenvironment, effectively recapitulating key features of ECM-mediated drug resistance. Mechanistic studies further demonstrated that DHCM significantly upregulates the expression of Aquaporin 3 (AQP3) in the encapsulated HCCs. This upregulation potentially activates mTOR signaling-associated autophagy pathways, thereby enhancing chemoresistance in HCCs. These biomimetic models provide a robust and versatile platform for studying the underlying mechanisms of drug resistance and evaluating therapeutic interventions. This innovative approach highlights the potential of DHCM/GelMA microgels as a transformative tool in cancer-associated tissue engineering and anticancer drug screening. By enabling detailed investigations into the role of ECM in chemoresistance, this study contributes to advancing therapeutic research and offers promising strategies to overcome drug resistance, ultimately improving clinical outcomes in liver cancer treatment.
肝癌是一种侵袭性很强的恶性肿瘤，由于其明显的化疗耐药性，在治疗管理方面仍然面临重大挑战。这种耐药性破坏了传统化疗和靶向治疗的疗效，其由多方面机制驱动，人们越来越重视肿瘤微环境（TME）的保护作用。肝细胞癌细胞外基质（ECM）是TME的主要非细胞成分，已成为癌症进展和耐药性的关键调节因子，尤其是在肝癌细胞（HCC）中。在本研究中，通过将脱细胞肝癌基质（DHCM）与甲基丙烯酸明胶（GelMA）前体整合，构建了一种混合仿生水凝胶。这种复合DHCM/GelMA水凝胶旨在复制肝癌细胞外基质的物理化学和功能特性，从而提供一个仿生平台来探索肝癌细胞与其微环境之间的相互作用。利用定制设计的微流控3D打印平台，我们实现了包裹肝癌细胞的DHCM/GelMA微凝胶的高通量制备，其特点是具有更高的均匀性、生物相容性和可扩展性。这些微凝胶促进了肝癌微组织的构建，随后用于化疗耐药性研究。我们的研究结果表明，DHCM/GelMA微凝胶紧密模拟肝癌肿瘤微环境，有效地重现了细胞外基质介导的耐药性的关键特征。机制研究进一步表明，DHCM显著上调包裹的肝癌细胞中 Aquaporin 3（AQP3）的表达。这种上调可能激活与mTOR信号相关的自噬途径，从而增强肝癌细胞的化疗耐药性。这些仿生模型为研究耐药性的潜在机制和评估治疗干预措施提供了一个强大而通用的平台。这种创新方法突出了DHCM/GelMA微凝胶作为癌症相关组织工程和抗癌药物筛选中变革性工具的潜力。通过能够详细研究细胞外基质在化疗耐药性中的作用，本研究有助于推进治疗研究，并提供克服耐药性的有前景策略，最终改善肝癌治疗的临床结果。
