Benčurová Katarína, Tran Loan, Friske Joachim, Bevc Kajetana, Helbich Thomas H, Hacker Marcus, Bergmann Michael, Zeitlinger Markus, Haug Alexander, Mitterhauser Markus, Egger Gerda, Balber Theresa
Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria.
EJNMMI Res. 2024 Sep 27;14(1):86. doi: 10.1186/s13550-024-01151-0.
Patient-derived tumour organoids (PDOs) are highly advanced in vitro models for disease modelling, yet they lack vascularisation. To overcome this shortcoming, organoids can be inoculated onto the chorioallantoic membrane (CAM); the highly vascularised, not innervated extraembryonic membrane of fertilised chicken eggs. Therefore, we aimed to (1) establish a CAM patient-derived xenograft (PDX) model based on PDOs generated from the liver metastasis of a colorectal cancer (CRC) patient and (2) to evaluate the translational pipeline (patient - in vitro PDOs - in vivo CAM-PDX) regarding morphology, histopathology, expression of C-X-C chemokine receptor type 4 (CXCR4), and radiotracer uptake patterns.
The main liver metastasis of the CRC patient exhibited high 2-[F]FDG uptake and moderate and focal [Ga]Ga-Pentixafor accumulation in the peripheral part of the metastasis. Inoculation of PDOs derived from this region onto the CAM resulted in large, highly viable, and extensively vascularised xenografts, as demonstrated immunohistochemically and confirmed by high 2-[F]FDG uptake. The xenografts showed striking histomorphological similarity to the patient's liver metastasis. The moderate expression of CXCR4 was maintained in ovo and was concordant with the expression levels of the patient's sample and in vitro PDOs. Following in vitro re-culturing of CAM-PDXs, growth, and [Ga]Ga-Pentixafor uptake were unaltered compared to PDOs before transplantation onto the CAM. Although [Ga]Ga-Pentixafor was taken up into CAM-PDXs, the uptake in the baseline and blocking group were comparable and there was only a trend towards blocking.
We successfully established an in vivo CAM-PDX model based on CRC PDOs. The histomorphological features and target protein expression of the original patient's tissue were mirrored in the in vitro PDOs, and particularly in the in vivo CAM-PDXs. The [Ga]Ga-Pentixafor uptake patterns were comparable between in vitro, in ovo and clinical data and 2-[F]FDG was avidly taken up in the patient's liver metastasis and CAM-PDXs. We thus propose the CAM-PDX model as an alternative in vivo model with promising translational value for CRC patients.
患者来源的肿瘤类器官（PDO）是用于疾病建模的高度先进的体外模型，但它们缺乏血管化。为克服这一缺点，可将类器官接种到鸡胚绒毛尿囊膜（CAM）上；CAM是受精鸡蛋高度血管化但无神经支配的胚外膜。因此，我们旨在：（1）基于一名结直肠癌（CRC）患者肝转移灶产生的PDO建立一种CAM患者来源异种移植（PDX）模型；（2）从形态学、组织病理学、C-X-C趋化因子受体4（CXCR4）表达及放射性示踪剂摄取模式方面评估转化流程（患者-体外PDO-体内CAM-PDX）。
CRC患者的主要肝转移灶表现出高2-[F]FDG摄取，且在转移灶周边部分有中度且局灶性的[Ga]Ga-喷替沙福蓄积。将源自该区域的PDO接种到CAM上可形成大的、高度存活且广泛血管化的异种移植物，免疫组化显示如此，并经高2-[F]FDG摄取得以证实。异种移植物在组织形态学上与患者的肝转移灶惊人地相似。CXCR4的中度表达在鸡胚内得以维持，且与患者样本及体外PDO的表达水平一致。在体外对CAM-PDX进行再培养后，其生长及[Ga]Ga-喷替沙福摄取与移植到CAM上之前的PDO相比未发生改变。尽管[Ga]Ga-喷替沙福被摄取到CAM-PDX中，但基线组和阻断组的摄取相当，仅存在阻断趋势。
我们成功建立了基于CRC PDO的体内CAM-PDX模型。原始患者组织的组织形态学特征和靶蛋白表达在体外PDO中得以体现，尤其在体内CAM-PDX中。体外、鸡胚内及临床数据中[Ga]Ga-喷替沙福的摄取模式具有可比性，且2-[F]FDG在患者肝转移灶及CAM-PDX中被大量摄取。因此，我们提出CAM-PDX模型作为一种对CRC患者具有潜在转化价值的替代体内模型。
