Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
Group of Bioengineering in Regeneration and Cancer, Biogipuzkoa Health Research Institute, San Sebastian, Spain.
Sci Adv. 2024 Nov 8;10(45):eadr3997. doi: 10.1126/sciadv.adr3997. Epub 2024 Nov 6.
Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery. Here, we explore dormancy-inducing 3D engineered matrices, which generate mechanical confinement and induce growth arrest and survival against chemotherapy in cancer cells. We characterized the dormant phenotype of solitary cells by P-ERK:P-p38 dormancy signaling ratio, along with Ki67 expression. As underlying mechanism, we identified stiffness-dependent nuclear localization of the four-and-a-half LIM domain 2 (FHL2) protein, leading to p53-independent high p21 nuclear expression, validated in murine and human tissue. Suggestive of a resistance-causing role, cells in the dormancy-inducing matrix became sensitive against chemotherapy upon FHL2 down-regulation. Thus, our biomaterial-based approach will enable systematic screens for previously unidentified compounds suited to eradicate potentially relapsing dormant cancer cells.
实体瘤即使经过局部和全身治疗，仍常出现远处转移和复发。细胞休眠已被确定为耐药的重要机制，使肿瘤能够在晚期复发。因此，对于看似无疾病的患者，那些来自不可见的、微小残留的癌症的复发，需要适合药物发现的休眠细胞的体外模型。在这里，我们探索了诱导休眠的 3D 工程基质，它可以产生机械限制，并在癌细胞中诱导对抗化疗的生长抑制和存活。我们通过 P-ERK：P-p38 休眠信号比以及 Ki67 表达来表征单个细胞的休眠表型。作为潜在的机制，我们发现四半LIM 结构域 2（FHL2）蛋白的核定位与刚度有关，导致 p53 非依赖性的高 p21 核表达，在鼠和人组织中得到了验证。有研究提示 FHL2 下调后，诱导休眠基质中的细胞对化疗变得敏感，这可能导致耐药。因此，我们基于生物材料的方法将能够对以前未识别的化合物进行系统筛选，以消灭可能复发的休眠癌细胞。
