Gudoityte Greta, Sharma Osheen, Leuenberger Laura, Wallin Emelie, Fernebro Josefin, Östling Päivi, Bergström Rebecka, Lindberg Johan, Joneborg Ulrika, Kallioniemi Olli, Seashore-Ludlow Brinton
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Mol Oncol. 2025 May 24. doi: 10.1002/1878-0261.70051.
Ovarian cancer (OC) is a leading cause of death of gynecological cancers in women. Poor patient response to treatment highlights the need to better understand how the tumor microenvironment affects OC progression. Growing evidence indicates the crucial role of non-cancerous components, such as cancer-associated fibroblasts, in establishing a complex network of cellular and molecular interactions, influencing cancer progression and response to treatment. Therefore, in this study, we sought to characterize the impact of fibroblasts on OC cell behavior and drug response. Using both direct and indirect cell co-culture systems, we observed distinct changes in cancer cell proliferation, morphology, and secretome in the presence of fibroblasts. Furthermore, an imaging-based high-throughput drug screen of 528 oncology compounds revealed multiple drugs that showed altered efficacy in the co-culture conditions, demonstrating the role of fibroblasts in driving cancer cell resistance to treatment. Most importantly, our data identified the two drug combinations of Birinapant or Vorinostat with Carboplatin as promising treatments, exploiting the altered cancer cell phenotype in co-cultures. These findings were supported by the increased sensitivity of ex vivo cultures to these combinations.
卵巢癌（OC）是女性妇科癌症死亡的主要原因。患者对治疗反应不佳凸显了更好地了解肿瘤微环境如何影响OC进展的必要性。越来越多的证据表明，诸如癌症相关成纤维细胞等非癌成分在建立复杂的细胞和分子相互作用网络、影响癌症进展和治疗反应方面起着关键作用。因此，在本研究中，我们试图描述成纤维细胞对OC细胞行为和药物反应的影响。使用直接和间接细胞共培养系统，我们观察到在有成纤维细胞存在的情况下，癌细胞增殖、形态和分泌组发生了明显变化。此外，对528种肿瘤化合物进行的基于成像的高通量药物筛选发现了多种在共培养条件下疗效改变的药物，证明了成纤维细胞在驱动癌细胞抗治疗方面的作用。最重要的是，我们的数据确定了比瑞那潘或伏立诺他与卡铂的两种药物组合是有前景的治疗方法，利用了共培养中改变的癌细胞表型。这些发现得到了体外培养对这些组合敏感性增加的支持。
