Steinbauer Silvia, Cowles Jamie D, Sabbaghi Mohammad Ali, Poppelaars Marle, Hussain Azaz, Wagesreither Marina, Laimer-Gruber Daniela, Tovari Jozsef, Szakacs Gergely, Csiszar Agnes
Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
Department of Biomedical Imaging and Image-Guided Therapy, Division of Structural and Molecular Preclinical Imaging, Medical University of Vienna, Vienna, Austria.
NPJ Breast Cancer. 2025 Jul 30;11(1):80. doi: 10.1038/s41523-025-00795-y.
Triple-negative breast cancer (TNBC) is associated with poor prognosis and high recurrence, driven by residual tumor cells that survive chemotherapy. To monitor therapy response in vivo, we established a clinically relevant TAC regimen (docetaxel, doxorubicin, cyclophosphamide) in mice bearing mammary tumors derived from K14cre;Brca1;Trp53 (KB1P) organoids expressing an mCherry-AkaLuc dual reporter (mCA-KB1P). AkaLuc bioluminescence imaging (AkaBLI) enabled non-invasive detection of minimal residual disease (MRD) with a sensitivity of approximately 1000 cells. As AkaLuc elicited an immune response, we generated Histon2B-mCherry-expressing KB1P organoids (HmC-KB1P) to study tumor cell survival in immunocompetent hosts. Flow cytometry and histological analysis revealed that MRD in immunocompetent mice is characterized by few residual cells with transient loss of epithelial markers, in contrast to immunodeficient hosts, which retains more epithelial-like cells. These findings validate AkaBLI for sensitive MRD detection and highlight the immune system's critical role in modulating residual tumor cell fate following chemotherapy.
三阴性乳腺癌（TNBC）与预后不良和高复发率相关，这是由化疗后存活的残留肿瘤细胞驱动的。为了在体内监测治疗反应，我们在携带源自K14cre;Brca1;Trp53（KB1P）类器官的乳腺肿瘤的小鼠中建立了一种临床相关的TAC方案（多西他赛、阿霉素、环磷酰胺），这些类器官表达mCherry-AkaLuc双报告基因（mCA-KB1P）。AkaLuc生物发光成像（AkaBLI）能够以约1000个细胞的灵敏度非侵入性检测微小残留病（MRD）。由于AkaLuc引发免疫反应，我们生成了表达组蛋白2B-樱桃红的KB1P类器官（HmC-KB1P），以研究免疫健全宿主中的肿瘤细胞存活情况。流式细胞术和组织学分析表明，与保留更多上皮样细胞的免疫缺陷宿主相比，免疫健全小鼠中的MRD特征是残留细胞较少且上皮标志物短暂丢失。这些发现验证了AkaBLI用于灵敏检测MRD，并突出了免疫系统在调节化疗后残留肿瘤细胞命运中的关键作用。
