Table 1_Histological fidelity and microenvironmental kinome signatures of metastatic patient-derived organoids.xlsx

Metastatic cancer remains the greatest clinical challenge due to ineffective treatments and limited reliable models for drug testing. Patient-derived organoids (PDOs) and their subsequent culture as patient-derived-organoid xenograft (PDOX) tumours have transformed cancer research by replicating the genetic and histological characteristics of primary tumours. However, less focus has been given to metastatic tumours. Here, we investigated how well kinase signalling was conserved in PDOs grown from core-needle biopsies isolated from metastatic tumour lesions of five cancer patients. We further compared changes in kinase signalling when these PDOs were grown as metastatic PDOX tumours in mice. Strikingly, PDOs retained much kinase signalling observed in the original tumour. Even more remarkable was the ability of the metastatic PDOX tumours to match both the signalling and morphological features of the original biopsy. Cross-sample analysis revealed lost Src Family Kinase signalling in PDO cultures, highlighting the important influence of the tumour microenvironment on signalling and demonstrating this can be partially restored in the in vivo setting. Together, these studies support the use of PDOs and derived PDOX in mimicking and modelling human metastatic tumour biology.

转移性癌症仍是当前临床面临的最大难题，其治疗手段有限且缺乏可靠的药物测试模型。患者来源类器官（Patient-derived Organoids，PDOs）及其衍生的患者来源类器官异种移植瘤（Patient-derived-organoid Xenograft，PDOX）模型可精准重现原发肿瘤的遗传与组织学特征，为癌症研究带来了革命性变革。然而，现有研究对转移性肿瘤的关注相对不足。本研究针对5名癌症患者转移性肿瘤病灶获取的核心针吸活检样本所培养的PDOs，探究了其激酶信号通路的保守程度。我们进一步对比了这些PDOs在小鼠体内构建转移性PDOX肿瘤时，其激酶信号通路的动态变化。值得注意的是，PDOs保留了原发肿瘤中绝大多数的激酶信号通路特征。更为亮眼的是，转移性PDOX肿瘤能够完美复刻原始活检样本的信号通路与形态学特征。跨样本分析显示，PDO培养体系中Src家族激酶（Src Family Kinase）的信号通路出现缺失，这凸显了肿瘤微环境对信号通路的关键调控作用，同时证明该通路缺失可在体内环境中得到部分恢复。综上，本研究证实PDOs及其衍生的PDOX模型可用于模拟并构建人类转移性肿瘤的生物学研究模型。