Development of a translational radiobiology platform using pancreatic cancer patient-derived organoids for personalized radiation oncology

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2025-09-17 DOI:10.1016/j.tranon.2025.102535

Christopher Kessler , Francheska Cadacio , Carlo Maurer , Arlett Schäfer , Felix Orben , Julius C. Fischer , Daniela Schilling , Lisa Fricke , Sebastian Rasch , Ihsan E. Demir , Katja Steiger , Wilko Weichert , Roland M. Schmid , Stephanie E. Combs , Maximilian Reichert , Sophie Dobiasch

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引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with neoadjuvant radio(chemo)therapy failing in approximately 70 % of cases due to high tumor heterogeneity, and intrinsic radioresistance. Patient-derived organoids (PDOs) closely recapitulate appearance, and functionality as the original tissue and have potential to explore novel therapies for personalized radiooncology.

In this study, the radioresponse of PDAC PDO lines was determined after irradiation (RT). PDOs were immunohistochemically characterized by γ-H2AX, HIF-1α and Ki-67 staining. RNA sequencing data were analyzed by gene set enrichment analyses to investigate underlying mechanisms of radioresistance. Preclinical findings were correlated with clinical data from the corresponding patients.

PDOs showed a significant heterogeneity in response to radiation and were classified into radiosensitive, intermediate, and radioresistant subgroups. A correlation between radiosensitivity and enhanced proliferation and decreased hypoxia was observed. OXPHOS-related gene signatures were significantly overexpressed in the radioresistant phenotype. Translationally, radioresistance in PDOs was associated with significantly poorer survival of patients.

Our platform demonstrated heterogeneity in radioresponse reflecting the clinical situation and correlation with clinical outcomes. Immunohistochemical staining and transcriptomic profiling identified molecular signatures, including HIF-1α and OXPHOS-related pathways, associated with radioresistance. Implementing PDO-based radioresponse profiling in clinical workflows may enable patient stratified treatment approaches. Overall, our findings suggest that functionalizing PDOs for radioresponse might extend PDO-informed precision oncology.

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胰腺癌患者衍生类器官用于个性化放射肿瘤学的转化放射生物学平台的开发。

胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤之一，由于肿瘤的高异质性和固有的放射耐药，新辅助放射治疗在大约70%的病例中失败。患者源性类器官（PDOs）与原始组织的外观和功能相似，具有探索个性化放射肿瘤学新疗法的潜力。本研究测定了PDAC PDO细胞系辐照后的放射反应（RT）。采用免疫组织化学方法对PDOs进行γ-H2AX、HIF-1α和Ki-67染色。通过基因集富集分析对RNA测序数据进行分析，以探讨辐射耐药的潜在机制。临床前发现与相应患者的临床数据相关。pdo对辐射的反应具有显著的异质性，分为放射敏感、中等和放射耐药亚组。观察到放射敏感性与增殖增强和缺氧减少之间的相关性。在辐射抗性表型中，oxphos相关基因显著过表达。翻译过来，pdo的放射耐药与患者的生存期明显较差相关。我们的平台显示了放射反应的异质性，反映了临床情况和与临床结果的相关性。免疫组织化学染色和转录组学分析鉴定了与放射耐药相关的分子特征，包括HIF-1α和oxphos相关途径。在临床工作流程中实施基于pdo的放射反应分析可能使患者分层治疗方法成为可能。总的来说，我们的研究结果表明，功能化pdo的放射反应可能会扩展pdo信息的精确肿瘤学。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.