PDF(Pubmed)
Abstract：
OBJECTIVE: In the pursuit of creating personalized and more effective treatment strategies for lung cancer patients, Patient-Derived Xenografts (PDXs) have been introduced as preclinical platforms that can recapitulate the specific patient\'s tumor in an in vivo model. We investigated how well PDX models can preserve the tumor\'s clinical and molecular characteristics across different generations.
METHODS: A Non-Small Cell Lung Cancer (NSCLC) PDX model was established in NSG-SGM3 mice and clinical and preclinical factors were assessed throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to create 20 patient-specific PDX models in NSG-SGM3 mice. Histopathological staining and Whole Exome Sequencing (WES) analysis were preformed to understand tumor heterogeneity throughout serial passages.
RESULTS: The main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to the long duration of chemotherapy treatment, which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of the histological type and grade; however, WES analysis revealed genomic instability in advanced passages, leading to the inconsistencies in clinically relevant alterations between the PDXs and biopsies.
CONCLUSIONS: Our study highlights the impact of multiple clinical and preclinical factors on the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs, and underscores the importance of considering these factors when guiding and evaluating prolonged personalized treatment studies for NSCLC patients in these models, as well as signaling the imperative for additional investigations to determine the full clinical potential of this technique.
METHODS: A Non-Small Cell Lung Cancer (NSCLC) PDX model was established in NSG-SGM3 mice and clinical and preclinical factors were assessed throughout subsequent passages. Our cohort consisted of 40 NSCLC patients, which were used to create 20 patient-specific PDX models in NSG-SGM3 mice. Histopathological staining and Whole Exome Sequencing (WES) analysis were preformed to understand tumor heterogeneity throughout serial passages.
RESULTS: The main factors that contributed to the growth of the engrafted PDX in mice were a higher grade or stage of disease, in contrast to the long duration of chemotherapy treatment, which was negatively correlated with PDX propagation. Successful PDX growth was also linked to poorer prognosis and overall survival, while growth pattern variability was affected by the tumor aggressiveness, primarily affecting the first passage. Pathology analysis showed preservation of the histological type and grade; however, WES analysis revealed genomic instability in advanced passages, leading to the inconsistencies in clinically relevant alterations between the PDXs and biopsies.
CONCLUSIONS: Our study highlights the impact of multiple clinical and preclinical factors on the engraftment success, growth kinetics, and tumor stability of patient-specific NSCLC PDXs, and underscores the importance of considering these factors when guiding and evaluating prolonged personalized treatment studies for NSCLC patients in these models, as well as signaling the imperative for additional investigations to determine the full clinical potential of this technique.
摘要：
目的：为了追求为肺癌患者创造个性化和更有效的治疗策略，患者来源的异种移植物（PDX）已被引入作为临床前平台，可以在体内模型中概括特定患者的肿瘤。我们研究了PDX模型在不同世代中如何很好地保留肿瘤的临床和分子特征。
方法：在NSG-SGM3小鼠中建立非小细胞肺癌（NSCLC）PDX模型，并在随后的传代中评估临床和临床前因素。我们的队列包括40例NSCLC患者，用于在NSG-SGM3小鼠中创建20个患者特异性PDX模型。进行组织病理学染色和全外显子组测序(WES)分析以了解整个连续传代的肿瘤异质性。
结果：导致小鼠移植PDX生长的主要因素是较高的疾病等级或阶段，与长期的化疗相反，与PDX传播呈负相关。成功的PDX生长也与较差的预后和总体生存率有关。虽然生长模式变异性受到肿瘤侵袭性的影响，主要影响第一段。病理分析显示保留了组织学类型和等级；然而，WES分析揭示了高级通道中的基因组不稳定性，导致PDX和活检之间的临床相关改变不一致。
结论：我们的研究强调了多种临床和临床前因素对植入成功的影响，生长动力学，和患者特异性NSCLCPDX的肿瘤稳定性，并强调了在这些模型中指导和评估NSCLC患者的长期个性化治疗研究时考虑这些因素的重要性，以及表明必须进行其他研究以确定该技术的全部临床潜力。
方法：在NSG-SGM3小鼠中建立非小细胞肺癌（NSCLC）PDX模型，并在随后的传代中评估临床和临床前因素。我们的队列包括40例NSCLC患者，用于在NSG-SGM3小鼠中创建20个患者特异性PDX模型。进行组织病理学染色和全外显子组测序(WES)分析以了解整个连续传代的肿瘤异质性。
结果：导致小鼠移植PDX生长的主要因素是较高的疾病等级或阶段，与长期的化疗相反，与PDX传播呈负相关。成功的PDX生长也与较差的预后和总体生存率有关。虽然生长模式变异性受到肿瘤侵袭性的影响，主要影响第一段。病理分析显示保留了组织学类型和等级；然而，WES分析揭示了高级通道中的基因组不稳定性，导致PDX和活检之间的临床相关改变不一致。
结论：我们的研究强调了多种临床和临床前因素对植入成功的影响，生长动力学，和患者特异性NSCLCPDX的肿瘤稳定性，并强调了在这些模型中指导和评估NSCLC患者的长期个性化治疗研究时考虑这些因素的重要性，以及表明必须进行其他研究以确定该技术的全部临床潜力。
