Schaier Martin, Baier Dina, Theiner Sarah, Berger Walter, Koellensperger Gunda
Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria.
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria.
JACS Au. 2025 Jun 11;5(6):2619-2631. doi: 10.1021/jacsau.5c00217. eCollection 2025 Jun 23.
Chemoresistance in cancer cells, particularly in refractory types, such as colorectal cancer, poses a major challenge to effective treatment. In particular, the interaction between cancer cells and the tumor microenvironment (TME) has been shown to exert substantial influence on the efficacy of therapeutic agents. This study investigated whether an intrinsic resistance phenotype alters drug distribution in the TME using xenograft models derived from HCT116 colorectal cancer cells, including oxaliplatin (OxPt)-sensitive and OxPt-resistant (OxR) variants. Tumors were prepared as formalin-fixed paraffin-embedded (FFPE) sections, followed by single-cell analysis with laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS). Based on histological evaluations, a panel of metal-conjugated antibodies was designed to target tissue architecture and distinct cell states within the TME. A dedicated calibration strategy was applied to accurately measure platinum (Pt) uptake in phenotypically defined single cells across both the tumor and its microenvironment. The results revealed substantial structural differences: HCT116/OxR tumors exhibited robust growth following drug administration, while parental tumors displayed extensive degradation. Notably, OxPt accumulated significantly in necrotic regions specific to HCT116/OxR, indicating resistance-dependent changes in drug compartmentalization. These findings suggest that an intrinsically resistant cancer cell phenotype is capable of markedly altering metal distributions within the TME.
癌细胞中的化学抗性，尤其是难治性类型的癌细胞，如结直肠癌，对有效治疗构成了重大挑战。特别是，癌细胞与肿瘤微环境（TME）之间的相互作用已被证明对治疗药物的疗效有重大影响。本研究使用源自HCT116结肠癌细胞的异种移植模型，包括对奥沙利铂（OxPt）敏感和对奥沙利铂耐药（OxR）的变体，研究了内在抗性表型是否会改变TME中的药物分布。将肿瘤制备成福尔马林固定石蜡包埋（FFPE）切片，然后用激光烧蚀电感耦合等离子体质谱仪（LA-ICP-TOFMS）进行单细胞分析。基于组织学评估，设计了一组金属偶联抗体，以靶向TME内的组织结构和不同的细胞状态。应用了一种专门的校准策略，以准确测量肿瘤及其微环境中表型定义的单细胞中的铂（Pt）摄取。结果显示出显著的结构差异：给药后，HCT116/OxR肿瘤表现出强劲生长，而亲本肿瘤则出现广泛降解。值得注意的是，OxPt在HCT116/OxR特有的坏死区域中显著积累，表明药物分隔存在抗性依赖性变化。这些发现表明，内在抗性癌细胞表型能够显著改变TME内的金属分布。
