Holthaus David, Rogmans Christoph, Gursinski Ina, Quevedo-Olmos Alvaro, Ehsani Marzieh, Mangler Mandy, Flörkemeier Inken, Weimer Jörg P, Meyer Thomas F, Maass Nicolai, Bauerschlag Dirk O, Hedemann Nina
Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany.
Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Front Oncol. 2024 Sep 2;14:1432239. doi: 10.3389/fonc.2024.1432239. eCollection 2024.
Cervical cancer represents one of the main causes of female, cancer-related mortality worldwide. The majority of cancers are caused by human papillomaviruses such as HPV16 and HPV18. As chemotherapeutic resistance to first-line platinum treatment is still a predominant clinical challenge in advanced cervical cancer, novel treatment options including combinatorial therapies are urgently required to overcome chemotherapeutic resistance. Inhibition of A Disintegrin And Metalloproteinase (ADAM)-family members, heavily involved in tumour progression of a vast range of solid tumours, strongly improved response to chemotherapeutic treatment in other tumour entities including ovarian cancer.
We established two- and three-dimensional models derived from three traditional cervical cancer cell lines and ectocervical cancer-derived organoids. Following characterisation, these models were used to investigate their response to cisplatin treatment in the absence and presence of ADAM inhibitors using viability assays and automated live cell imaging.
The pivotal role of the metalloprotease ADAM17 driving chemotherapy resistance was detectable in all ectocervical cultures irrespective of the model system used, whereas ADAM10 inhibition was predominantly effective only in loosely aggregated spheroids. We showed prominent differences regarding treatment responses between 2D monolayers compared to 3D spheroid and 3D organoid model systems. Particularly, the organoid system, regarded as the closest representation of primary tumours, exhibited reliably the combinatorial effect of ADAM17 inhibition and cisplatin in all three individual donors.
As two- and three-dimensional models of the same cell lines differ in their responses to chemotherapy it is essential to validate treatment strategies in more advanced model systems representing the patient situation more realistically. Ectocervical organoids showed reliable results regarding treatment responses closely mimicking the primary tumours and could therefore serve as an important tool for personalized medicine in cervical cancer. These findings strengthen the role of ADAM17 as a potential novel target for combinatorial treatments to overcome chemoresistance in cervical cancer.
宫颈癌是全球女性癌症相关死亡的主要原因之一。大多数癌症是由人乳头瘤病毒引起的，如HPV16和HPV18。由于对一线铂类治疗的化疗耐药性仍是晚期宫颈癌的主要临床挑战，因此迫切需要包括联合疗法在内的新治疗方案来克服化疗耐药性。抑制在多种实体瘤的肿瘤进展中起重要作用的解整合素和金属蛋白酶（ADAM）家族成员，可显著改善包括卵巢癌在内的其他肿瘤实体对化疗的反应。
我们建立了源自三种传统宫颈癌细胞系和宫颈外癌衍生类器官的二维和三维模型。在进行表征后，使用活力测定和自动活细胞成像，利用这些模型研究它们在不存在和存在ADAM抑制剂的情况下对顺铂治疗的反应。
无论使用何种模型系统，在所有宫颈外培养物中均可检测到金属蛋白酶ADAM17在驱动化疗耐药性方面的关键作用，而抑制ADAM10仅在松散聚集的球体中主要有效。我们发现二维单层与三维球体和三维类器官模型系统在治疗反应方面存在显著差异。特别是，被视为最接近原发性肿瘤的类器官系统，在所有三个个体供体中均可靠地展现了ADAM17抑制和顺铂的联合作用。
由于同一细胞系的二维和三维模型对化疗的反应不同，因此在更能真实反映患者情况的更先进模型系统中验证治疗策略至关重要。宫颈外类器官在治疗反应方面显示出可靠的结果，与原发性肿瘤非常相似，因此可作为宫颈癌个性化医疗的重要工具。这些发现强化了ADAM17作为联合治疗以克服宫颈癌化疗耐药性的潜在新靶点的作用。
