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Establishing 3D organoid models from patient-derived conditionally reprogrammed cells to bridge preclinical and clinical insights in pancreatic cancer. ​

文献信息 ​

DOI10.1186/s12943-025-02374-y
PMID40462147
期刊Molecular cancer
影响因子33.9
JCR 分区Q1
发表年份2025
被引次数1
关键词3D类器官培养, 条件重编程细胞（CRC）类器官, 药物敏感性筛选, FOLFIRINOX, 吉西他滨联合纳米白蛋白紫杉醇（Abraxane）
文献类型Journal Article
ISSN1476-4598
页码162
期号24(1)
作者Jin Su Kim, Chan Hee Park, Eunyoung Kim, Hee Seung Lee, Jinyoung Lee, Jeehoon Kim, Eun Hee Kam, Sanghee Nam, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Sangwoo Kim, Galam Leem, Seungmin Bang

一句话小结 ​

本研究开发了一种基于患者来源条件重编程细胞的三维类器官模型，以克服传统二维培养模型的局限性，发现3D类器官能够更准确地反映胰腺癌患者的临床药物反应。该模型为临床前药物评估提供了有效平台，有助于识别预测性生物标志物，推动胰腺癌精准医学的发展。

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3D类器官培养 · 条件重编程细胞（CRC）类器官 · 药物敏感性筛选 · FOLFIRINOX · 吉西他滨联合纳米白蛋白紫杉醇（Abraxane）

摘要 ​

背景
胰腺癌是一种致死率极高的恶性肿瘤，对治疗的反应有限。尽管治疗方法有所进展，但系统性化疗仍然是超过80%患者的主要治疗手段，目前尚未建立指导药物选择的生物标志物。传统的二维（2D）培养模型无法再现肿瘤微环境，因此需要开发更先进的模型，如三维（3D）类器官模型。

方法
我们使用患者来源的条件重编程细胞（CRC）系建立了3D类器官培养，这些细胞最初在2D条件下培养。这些CRC类器官是在不使用特定于类器官培养基成分的Matrigel基础平台上开发的，以保留细胞的内在分子亚型。我们进行了形态学、分子和药物敏感性分析，以比较3D CRC类器官与其2D对照及临床反应的临床响应。

结果
3D CRC类器官保留了母肿瘤的分子特征、转录组和突变谱，并显示出与癌症阶段和分化相关的不同形态。对吉西他滨联合纳米白蛋白紫杉醇（Abraxane）和FOLFIRINOX的药物反应分析显示，3D类器官比2D培养更准确地反映了患者的临床反应。值得注意的是，3D类器官的IC50值通常较高，反映了在体内观察到的结构复杂性和药物渗透障碍。

结论
基于Matrigel的3D类器官培养模型为临床前药物评估提供了一个强有力的平台，克服了2D模型的局限性。尽管耗时且资源密集，但将2D和3D平台结合使用可以实现高效的初步筛选和验证。这种方法有望识别预测性生物标志物，并推动胰腺癌治疗中的精准医学发展。

英文摘要 ​

BACKGROUND Pancreatic cancer is a highly lethal malignancy with limited treatment response. Despite advancements in treatment, systemic chemotherapy remains the primary therapeutic approach for over 80% of patients, with no established biomarkers to guide drug selection. Traditional two-dimensional (2D) culture models fail to replicate the tumor microenvironment, necessitating the development of more advanced models, such as three-dimensional (3D) organoid models.

METHODS We established 3D organoid cultures using patient-derived conditionally reprogrammed cell (CRC) lines, originally cultured under 2D conditions. These CRC organoids were developed using a Matrigel-based platform without organoid-specific medium components to preserve the intrinsic molecular subtypes of the cells. Morphological, molecular, and drug sensitivity analyses were performed to compare the clinical responses of 3D CRC organoids with those of their 2D counterparts and clinical responses.

RESULTS The 3D CRC organoids retained the molecular characteristics, transcriptomic and mutational profiles of the parental tumors and displayed distinct morphologies corresponding to cancer stages and differentiation. Drug response profiling of gemcitabine plus nab-paclitaxel (Abraxane) and FOLFIRINOX demonstrated that the 3D organoids more accurately mirrored patient clinical responses than the 2D cultures. Notably, the IC50 values for the 3D organoids were generally higher, reflecting the structural complexity and drug penetration barriers observed in vivo.

CONCLUSION Matrigel-based 3D organoid culture models provide a robust platform for pre-clinical drug evaluation, overcoming the limitations of 2D models. Although time- and resource-intensive, integrating both 2D and 3D platforms enables efficient initial screening and validation. This approach holds promise for identifying predictive biomarkers and advancing precision medicine in pancreatic cancer treatment.

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主要研究问题 ​

  1. 3D类器官模型在其他类型癌症研究中的应用有哪些成功案例？
  2. 条件重编程细胞在不同肿瘤类型中的应用潜力如何？
  3. 3D类器官模型的构建过程中，如何优化培养基成分以更好地模拟肿瘤微环境？
  4. 通过3D类器官模型进行的药物敏感性分析，如何提高其预测临床反应的准确性？
  5. 在精准医疗中，如何结合3D类器官模型与其他生物标志物的研究以改善治疗方案？

核心洞察 ​

研究背景和目的 ​

胰腺癌是一种致死率极高的恶性肿瘤，目前的治疗反应有限。尽管治疗方法有所进展，系统性化疗仍然是超过80%患者的主要治疗手段，但尚无确立的生物标志物用于指导药物选择。传统的二维（2D）培养模型无法有效模拟肿瘤微环境，因此需要开发更先进的三维（3D）类器官模型。

主要方法/材料/实验设计 ​

本研究建立了基于患者来源的条件重编程细胞（CRC）系的3D类器官培养。最初在2D条件下培养的CRC细胞，采用不含特定类器官培养基成分的Matrigel平台进行发展，以保留细胞的内在分子亚型。研究通过形态学、分子分析和药物敏感性分析，对比3D CRC类器官与其2D对应物及临床反应的差异。

Mermaid diagram

关键结果和发现 ​

  • 3D CRC类器官保留了原肿瘤的分子特征、转录组和突变谱，并表现出与癌症阶段和分化相对应的不同形态。
  • 对吉西他滨加纳米紫杉醇（Abraxane）和FOLFIRINOX的药物反应分析显示，3D类器官更准确地反映了患者的临床反应，相较于2D培养，3D类器官的IC50值普遍较高，反映出体内观察到的结构复杂性和药物渗透障碍。

主要结论/意义/创新性 ​

Matrigel基于的3D类器官培养模型为临床前药物评估提供了一个强有力的平台，克服了2D模型的局限性。尽管这一方法在时间和资源上较为密集，但将2D和3D平台结合使用，可以有效进行初步筛选和验证。这一方法有望帮助识别预测生物标志物，并推动胰腺癌治疗的精准医学发展。

研究局限性和未来方向 ​

  • 研究的局限性在于3D类器官培养时间较长且资源消耗较大，可能限制其广泛应用。
  • 未来的研究方向包括进一步优化3D类器官培养条件，提高其高通量筛选能力，以及探索与临床数据的更深层次关联，以推动精准医学的实现。

参考文献 ​

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引用本文的文献 ​

  1. Cell and tissue reprogramming: Unlocking a new era in medical drug discovery. - Chandan K Sen;Andrew J Friday;Sashwati Roy - Pharmacological reviews (2025)

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