Ravi Preetham, Ghosh Shrinwanti, Pashaki Pooyan Vahidi, Shetty Kalidas, Kim Jiha, Gaba Anu, Katti Dinesh R, Katti Kalpana S
Department of Civil Construction and Environmental Engineering, North Dakota State University, Fargo, North Dakota 58108, United States.
Department of Biological Sciences, North Dakota State University, Fargo, North Dakota 58108, United States.
ACS Biomater Sci Eng. 2025 May 12;11(5):2824-2833. doi: 10.1021/acsbiomaterials.4c01599. Epub 2025 Apr 1.
As breast cancer progresses to stage IV, it metastasizes to secondary organs, with a strong propensity for bone colonization. Bone metastasis results in dramatically decreased survival rates and currently lacks a definitive cure. To improve survival rates significantly, there is a need for complex and precise models that can accurately replicate advanced-stage breast cancer for drug screening purposes. Previously, we established a 3D nanoclay model of bone metastatic breast cancer using human mesenchymal stem cells in combination with either commercial breast cancer cells (MCF-7 and MDA-MB-231) or patient-derived cells (NT013 and NT023) from the primary breast cancer site. In the present study, the efficacy of the model to distinguish and differentiate between the severity of metastasis in a total of eight patient-derived cell lines representing various subtypes was evaluated. We also tested the effects of the phytochemically enriched plant extract, in bone metastatic (BM) culture. Our results confirmed that the cell lines maintained their subtype-specific characteristics after isolation and formed tumors within the bone microenvironment. Additionally, we assessed the impact of these cell lines on Wnt signaling pathways, identifying which lines upregulate or downregulate Wnt signaling through ET-1 and DKK-1 cytokine levels. Within each subtype, we observed differences in the severity of metastasis between patients. induced cytotoxicity in most patient-derived BM cultures, though NT042 BM cultures showed minimal response. In summary, our study has established a patient-derived bone-metastatic breast cancer model that is well-suited for personalized drug screening aimed at treating late-stage breast cancer. This bone metastatic testbed has the capability to evaluate the severity of metastasis within breast cancer subtypes for individual patients.
随着乳腺癌发展到IV期，它会转移到继发器官，尤其容易在骨骼中定植。骨转移导致生存率大幅下降，目前尚无根治方法。为了显著提高生存率，需要复杂而精确的模型，能够准确复制晚期乳腺癌用于药物筛选。此前，我们使用人间充质干细胞与商业乳腺癌细胞（MCF-7和MDA-MB-231）或来自原发性乳腺癌部位的患者来源细胞（NT013和NT023）建立了骨转移性乳腺癌的3D纳米粘土模型。在本研究中，评估了该模型区分和鉴别代表各种亚型的总共八种患者来源细胞系中转移严重程度的能力。我们还测试了富含植物化学物质的植物提取物在骨转移（BM）培养中的作用。我们的结果证实，这些细胞系在分离后保持其亚型特异性特征，并在骨微环境中形成肿瘤。此外，我们评估了这些细胞系对Wnt信号通路的影响，确定哪些细胞系通过ET-1和DKK-1细胞因子水平上调或下调Wnt信号。在每个亚型中，我们观察到患者之间转移严重程度的差异。在大多数患者来源的BM培养物中诱导了细胞毒性，尽管NT042 BM培养物显示出最小的反应。总之，我们的研究建立了一种患者来源的骨转移性乳腺癌模型，非常适合用于治疗晚期乳腺癌的个性化药物筛选。这个骨转移试验台有能力评估个体患者乳腺癌亚型内转移的严重程度。
