Kratz Jeremy D, Rehman Shujah, Johnson Katherine A, Gillette Amani A, Sunil Aishwarya, Favreau Peter F, Pasch Cheri A, Miller Devon, Zarling Lucas C, Yeung Austin H, Clipson Linda, Anderson Samantha J, Steimle Alyssa K, Sprackling Carley M, Lemmon Kayla K, Abbott Daniel E, Burkard Mark E, Bassetti Michael F, Eickhoff Jens C, Foley Eugene F, Heise Charles P, Kimple Randall J, Lawson Elise H, LoConte Noelle K, Lubner Sam J, Mulkerin Daniel L, Matkowskyj Kristina A, Sanger Cristina B, Uboha Nataliya V, Mcilwain Sean J, Ong Irene M, Carchman Evie H, Skala Melissa C, Deming Dustin A
Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, School of Medicine and Public Health, University of Wisconsin, University of Wisconsin, Madison, WI, USA.
Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Sci Rep. 2025 Apr 9;15(1):12072. doi: 10.1038/s41598-025-96204-2.
Tumor heterogeneity is predicted to confer inferior clinical outcomes with precision-based strategies, however, modeling heterogeneity in a manner that still represents the tumor of origin remains a formidable challenge. Sequencing technologies are limited in their ability to identify rare subclonal populations and predict response to treatments for patients. Patient-derived organotypic cultures have significantly improved the modeling of cancer biology by faithfully representing the molecular features of primary malignant tissues. Patient-derived cancer organoid (PCO) cultures contain subclonal populations with the potential to recapitulate heterogeneity, although treatment response assessments commonly ignore diversity in the molecular profile or treatment response. Here, we demonstrate the advantage of evaluating individual PCO heterogeneity to enhance the sensitivity of these assays for predicting clinical response. Additionally, organoid subcultures identify subclonal populations with altered treatment response. Finally, dose escalation studies of PCOs to targeted anti-EGFR therapy are utilized which reveal divergent pathway expression when compared to pretreatment cultures. Overall, these studies demonstrate the importance of population-based organoid response assessments, the use of PCOs to identify molecular heterogeneity not observed with bulk tumor sequencing, and PCO heterogeneity for understanding therapeutic resistance mechanisms.
肿瘤异质性预计会使基于精准的策略带来较差的临床结果，然而，以一种仍能代表原发肿瘤的方式对异质性进行建模仍然是一项艰巨的挑战。测序技术在识别罕见亚克隆群体以及预测患者对治疗的反应方面能力有限。患者来源的器官型培养物通过忠实地呈现原发性恶性组织的分子特征，显著改善了癌症生物学的建模。患者来源的癌症类器官（PCO）培养物包含具有概括异质性潜力的亚克隆群体，尽管治疗反应评估通常忽略分子谱或治疗反应中的多样性。在此，我们展示了评估单个PCO异质性以提高这些检测预测临床反应敏感性的优势。此外，类器官传代培养可识别治疗反应发生改变的亚克隆群体。最后，利用PCO针对靶向抗表皮生长因子受体（EGFR）治疗的剂量递增研究，结果显示与预处理培养物相比，其通路表达存在差异。总体而言，这些研究证明了基于群体的类器官反应评估的重要性、利用PCO识别在肿瘤整体测序中未观察到的分子异质性以及PCO异质性对于理解治疗耐药机制的重要性。
