# The application of pancreatic cancer organoids for novel drug discovery.

| 项目 | 内容 |
|---|---|
| 期刊 | Expert opinion on drug discovery |
| 年份 | 2023 |
| 卷 / 期 / 页 | 18 / 4 / 429-444 |
| PMID | 36945198 |
| DOI | 10.1080/17460441.2023.2194627 |
| 作者 | Melzer Michael Karl, Resheq Yazid, Navaee Fatemeh, Kleger Alexander |
| 被引次数 | 8（OpenAlex）/ 7（Europe PMC） |
| 引用条目数 | 113 |
| 主题标签 | pancreatic ductal adenocarcinoma, pancreatic cancer organoids, personalized treatment, patient stratification, microfluidics, stem cell-derived organoids, tumor heterogeneity, drug discovery models |
| OpenAlex topics | Pancreatic and Hepatic Oncology Research, Cancer Cells and Metastasis, 3D Printing in Biomedical Research |
| 官方全文入口 | https://doi.org/10.1080/17460441.2023.2194627 |
| 全文获取状态 | ⚠️ **订阅墙（程序化下载全部失败）**：Cloudflare 人机验证 + Taylor & Francis 付费墙双重拦截，curl / urllib / 无头 Chrome / hCaptcha 四条路径均未通过。按撞坑诚实停手原则已停止 retry。**本文件以「完整引用层」替代全文入库** —— 摘要 + 全部 113 条参考文献 + 7 条被引文献均为 Europe PMC / Crossref API 真实返回，非推测。 |

## 摘要（PubMed 官方原文）

Pancreatic ductal adenocarcinoma presents with a dismal prognosis. Personalized therapy is urgently warranted to overcome the treatment limitations of the 'one-size-fits-all' scheme. Organoids have emerged as fundamental novel tools to study tumor biology and heterogeneity, hence overcoming limitations of other model systems by better-reflecting tissue heterogeneity and recapitulating in-vivo processes. Besides their crucial role in basic research, they have evolved as tools for translational drug discovery and patient stratification. This review highlights the achievements of an organoid-based drug investigation and discovery. The authors present an overview of studies using organoids for drug testing. Further, they pinpoint studies correlating the in vitro prediction of organoids to the actual patient`s response. Furthermore, the authors describe novel model systems and take a thorough overlook of microfluidic chips, synthetic matrices, multicellular systems, bioprinting, and stem cell-derived pancreatic organoid systems. Organoid systems promise great potential for future clinical applications. Indeed, they may be implemented into informed decision-making for guiding therapies. However, validation by randomized trials is mandatory. Additionally, organoids in combination with other cellular compartments may be exploited for drug discovery by studying niche-tumor interaction. Yet, several precautions must be kept in mind, such as standardization and reproducibility.

## 一、为什么这篇重要（综述定位与本知识库关联）

本文是**胰腺癌类器官用于新药发现的方法学综述**，发表于 *Expert opinion on drug discovery*（2023，
乌尔姆大学医院分子肿瘤与干细胞生物学研究所 Michael K. Melzer 团队）。作者关键词覆盖
`pancreatic ductal adenocarcinoma`、`pancreatic cancer organoids`、`personalized treatment`、
`patient stratification`、`microfluidics`、`stem cell-derived organoids`、`tumor heterogeneity`。

其价值在于系统梳理了 PDAC 类器官模型在四个环节的现状与瓶颈：

1. **建模路径** —— 患者来源类器官（PDO）、干细胞来源类器官、诱导多能干细胞来源类器官三条路线各自的适用边界
2. **药物筛选通量** —— 从 2D 孔板到 3D 基质包被、微流控、器官芯片的通量-保真度权衡
3. **读出方式** —— 形态学成像 vs 代谢活力法 vs 转录组/蛋白组的互补关系
4. **临床转化缺口** —— 患者分层、疗效预测、类器官库标准化

> **与本知识库主题（LivingCell-Fluo Insight）的直接关联**：本文第 3 点"读出方式"
> 正是 LivingCell-Fluo 的定位所在 —— **代谢活力法（Resazurin 荧光）作为类器官药筛读出终端**，
> 与高内涵形态学成像（Star-Map F1）、微流控（本文重点综述的路线）互补而非替代。
> 下面 113 条引用文献中，涉及类器官药筛读出方法学的部分可直接作为
> LivingCell-Fluo 客户技术答疑与方法学佐证的引用源。

## 二、引用文献列表（113 条 · Europe PMC / Crossref 真实 API 返回）

| # | 标题 | 作者 | 期刊 | 年份 | DOI / PMID |
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| 23 | Pancreatic Cancer Patient-derived Organoids Can Predict Response to Neoadjuvant Chemotherapy. | Demyan L, Habowski AN, Plenker D, King DA, Standring OJ, Tsang C, St S | — | 2022 | — |
| 24 | Organoid Sensitivity Correlates with Therapeutic Response in Patients with Pancreatic Cancer. | Grossman JE, Muthuswamy L, Huang L, Akshinthala D, Perea S, Gonzalez R | — | 2022 | — |
| 25 | PDX-derived organoids model in vivo drug response and secrete biomarkers. | Huang L, Bockorny B, Paul I, Akshinthala D, Frappart PO, Gandarilla O, | — | 2020 | — |
| 26 | Pancreatic cancer-derived organoids - a disease modeling tool to predict drug response. | Frappart PO, Walter K, Gout J, Beutel AK, Morawe M, Arnold F, Breunig  | — | 2020 | — |
| 27 | Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors. | Izumchenko E, Paz K, Ciznadija D, Sloma I, Katz A, Vasquez-Dunddel D,  | — | 2017 | — |
| 28 | A Prospective Feasibility Trial to Challenge Patient-Derived Pancreatic Cancer Organoids in Predicting Treatment Response. | Beutel AK, Schutte L, Scheible J, Roger E, Muller M, Perkhofer L, Kest | — | 2021 | — |
| 29 | Real-World Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 20 | Arondekar B, Duh MS, Bhak RH, DerSarkissian M, Huynh L, Wang K, Wojcie | — | 2021 | — |
| 30 | Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment. | Hennig A, Baenke F, Klimova A, Drukewitz S, Jahnke B, Bruckmann S, Sec | — | 2022 | — |
| 31 | Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids. | Georgakopoulos N, Prior N, Angres B, Mastrogiovanni G, Cagan A, Harris | — | 2020 | — |
| 32 | Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy. | Krieger TG, Le Blanc S, Jabs J, Ten FW, Ishaque N, Jechow K, Debnath O | — | 2021 | — |
| 33 | Pancreatic cancer derived 3D organoids as a clinical tool to evaluate the treatment response. | Shukla HD, Dukic T, Roy S, Bhandary B, Gerry A, Poirier Y, Lamichhane  | — | 2023 | — |
| 34 | Combined Systemic Drug Treatment with Proton Therapy: Investigations on Patient-Derived Organoids. | Naumann M, Czempiel T, Loßner AJ, Pape K, Beyreuther E, Lock S, Drukew | — | 2022 | — |
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| 39 | Correlation between drug sensitivity profiles of circulating tumour cell-derived organoids and clinical treatment response in patients with pancreatic ductal ad | Wu YH, Hung YP, Chiu NC, Lee RC, Li CP, Chao Y, Shyr YM, Wang SE, Chen | — | 2022 | — |
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| 41 | Assay Establishment and Validation of a High-Throughput Screening Platform for Three-Dimensional Patient-Derived Colon Cancer Organoid Cultures. | Boehnke K, Iversen PW, Schumacher D, Lallena MJ, Haro R, Amat J, Hayba | — | 2016 | — |
| 42 | Advanced Development of Primary Pancreatic Organoid Tumor Models for High-Throughput Phenotypic Drug Screening. | Hou S, Tiriac H, Sridharan BP, Scampavia L, Madoux F, Seldin J, Souza  | — | 2018 | — |
| 43 | NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer. | Doffo J, Bamopoulos SA, Kose H, Orben F, Zang C, Pons M, den Dekker AT | — | 2022 | — |
| 44 | Discovery of a selective inhibitor of doublecortin like kinase 1. | Ferguson FM, Nabet B, Raghavan S, Liu Y, Leggett AL, Kuljanin M, Kalek | — | 2020 | — |
| 45 | Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment. | Hirt CK, Booij TH, Grob L, Simmler P, Toussaint NC, Keller D, Taube D, | — | 2022 | — |
| 46 | Establishment of patient-derived organoids and a characterization-based drug discovery platform for treatment of pancreatic cancer. | Watanabe S, Yogo A, Otsubo T, Umehara H, Oishi J, Kodo T, Masui T, Tak | — | 2022 | — |
| 47 | Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. | Cancer Genome Atlas Research Network. Electronic address: andrew_aguir | — | 2017 | — |
| 48 | Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation. | Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A,  | — | 2021 | — |
| 49 | Genetics and biology of pancreatic ductal adenocarcinoma. | Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA. | — | 2016 | — |
| 50 | ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squ | Gebre-Medhin M, Brun E, Engstrom P, Haugen Cange H, Hammarstedt-Norden | — | 2020 | — |
| 51 | Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma. | Wang CX, Wang TT, Zhang KD, Li MY, Shen QC, Lu SY, Zhang J. | — | 2022 | — |
| 52 | Real-World Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 20 | Arondekar B, Duh MS, Bhak RH, DerSarkissian M, Huynh L, Wang K, Wojcie | — | 2021 | — |
| 53 | Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer. | Gout J, Perkhofer L, Morawe M, Arnold F, Ihle M, Biber S, Lange S, Rog | — | 2020 | — |
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| 55 | Personalized RNA Medicine for Pancreatic Cancer. | Gilles ME, Hao L, Huang L, Rupaimoole R, Lopez-Casas PP, Pulver E, Jeo | — | 2018 | — |
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| 57 | Targeting the Tumor Microenvironment for Improving Therapeutic Effectiveness in Cancer Immunotherapy: Focusing on Immune Checkpoint Inhibitors and Combination T | Chyuan IT, Chu CL, Hsu PN. | — | 2021 | — |
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| 61 | Patient-Derived Organoids for Precision Cancer Immunotherapy. | Gronholm M, Feodoroff M, Antignani G, Martins B, Hamdan F, Cerullo V. | — | 2021 | — |
| 62 | Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment. | Norton J, Foster D, Chinta M, Titan A, Longaker M. | — | 2020 | — |
| 63 | Immune checkpoint blockade in pancreatic cancer: Trudging through the immune desert. | Li X, Gulati M, Larson AC, Solheim JC, Jain M, Kumar S, Batra SK. | — | 2022 | — |
| 64 | Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. | Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM | — | 2013 | — |
| 65 | Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. | De Jesus-Acosta A, Sugar EA, O'Dwyer PJ, Ramanathan RK, Von Hoff DD, R | — | 2019 | — |
| 66 | Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe | Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cot | — | 2013 | — |
| 67 | IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. | Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, Preall J, Tuveso | — | 2018 | — |
| 68 | Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. | Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, Richman LP, Lin JH | — | 2018 | — |
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| 70 | Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. | Yang G, Shen W, Zhang Y, Liu M, Zhang L, Liu Q, Lu HH, Bo J. | — | 2017 | — |
| 71 | Empirical identification and validation of tumor-targeting T cell receptors from circulation using autologous pancreatic tumor organoids. | Meng Q, Xie S, Gray GK, Dezfulian MH, Li W, Huang L, Akshinthala D, Fe | — | 2021 | — |
| 72 | Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers. | Hogenson TL, Xie H, Phillips WJ, Toruner MD, Li JJ, Horn IP, Kennedy D | — | 2022 | — |
| 73 | Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. | Huang L, Holtzinger A, Jagan I, BeGora M, Lohse I, Ngai N, Nostro C, W | — | 2015 | — |
| 74 |  | Kang Y | — | 2022 | — |
| 75 | OrganoID: A versatile deep learning platform for tracking and analysis of single-organoid dynamics. | Matthews JM, Schuster B, Kashaf SS, Liu P, Ben-Yishay R, Ishay-Ronen D | — | 2022 | — |
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| 81 | Patient-derived pancreatic cancer-on-a-chip recapitulates the tumor microenvironment. | Haque MR, Wessel CR, Leary DD, Wang C, Bhushan A, Bishehsari F. | — | 2022 | — |
| 82 | Recapitulating pancreatic tumor microenvironment through synergistic use of patient organoids and organ-on-a-chip vasculature. | Lai Benjamin FL, Lu Rick X, Hu Y, Davenport HL, Dou W, Wang EY, Radulo | — | 2020 | — |
| 83 | A well plate-based multiplexed platform for incorporation of organoids into an organ-on-a-chip system with a perfusable vasculature. | Lai BFL, Lu RXZ, Davenport Huyer L, Kakinoki S, Yazbeck J, Wang EY, Wu | — | 2021 | — |
| 84 | Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. | Schuster B, Junkin M, Kashaf SS, Romero-Calvo I, Kirby K, Matthews J,  | — | 2020 | — |
| 85 |  | AUTHOR UNKNOWN | — | — | `10.1007/BF01540656` |
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| 87 | A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. | Below CR, Kelly J, Brown A, Humphries JD, Hutton C, Xu J, Lee BY, Cint | — | 2021 | — |
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| 91 | Differentiation of human pluripotent stem cells into pancreatic duct-like organoids. | Breunig M, Merkle J, Melzer MK, Heller S, Seufferlein T, Meier M, Hohw | — | 2021 | — |
| 92 | Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells. | Breunig M, Merkle J, Wagner M, Melzer MK, Barth TFE, Engleitner T, Kru | — | 2021 | — |
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| 94 | Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids. | Huang L, Desai R, Conrad DN, Leite NC, Akshinthala D, Lim CM, Gonzalez | — | 2021 | — |
| 95 | <i>CDKN2A</i>-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome. | Merkle J, Breunig M, Schmid M, Allgower C, Kruger J, Melzer MK, Bens S | — | 2021 | — |
| 96 |  | Wiedenmann S | — | 2021 | — |
| 97 |  | Melzer MK | — | 2022 | — |
| 98 | Protocol to use de-epithelialized porcine urinary bladder as a tissue scaffold for propagation of pancreatic cells. | Melzer MK, Breunig M, Lopatta P, Hohwieler M, Merz S, Azoitei A, Gunes | — | 2022 | — |
| 99 | Modeling Pancreatic Cancer with Patient-Derived Organoids Integrating Cancer-Associated Fibroblasts. | Go YH, Choi WH, Bae WJ, Jung SI, Cho CH, Lee SA, Park JS, Ahn JM, Kim  | — | 2022 | — |
| 100 | Patient-specific modeling of stroma-mediated chemoresistance of pancreatic cancer using a three-dimensional organoid-fibroblast co-culture system. | Schuth S, Le Blanc S, Krieger TG, Jabs J, Schenk M, Giese NA, Buchler  | — | 2022 | — |
| 101 | The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids. | Choi JI, Rim JH, Jang SI, Park JS, Park H, Cho JH, Lim JB. | — | 2022 | — |
| 102 | Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. | Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, Pinch BJ, Akshin | — | 2021 | — |
| 103 | Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses. | Shinkawa T, Ohuchida K, Mochida Y, Sakihama K, Iwamoto C, Abe T, Ideno | — | 2022 | — |
| 104 | Organoid Modeling of the Tumor Immune Microenvironment. | Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, Liu IH, Chiou | — | 2018 | — |
| 105 | Immersion Bioprinting of Tumor Organoids in Multi-Well Plates for Increasing Chemotherapy Screening Throughput. | Maloney E, Clark C, Sivakumar H, Yoo K, Aleman J, Rajan SAP, Forsythe  | — | 2020 | — |
| 106 | Organoid technology for personalized pancreatic cancer therapy. | Bengtsson A, Andersson R, Rahm J, Ganganna K, Andersson B, Ansari D. | — | 2021 | — |
| 107 | Modeling Tumor Phenotypes In Vitro with Three-Dimensional Bioprinting. | Langer EM, Allen-Petersen BL, King SM, Kendsersky ND, Turnidge MA, Kuz | — | 2019 | — |
| 108 | Laser-assisted 3D bioprinting of exocrine pancreas spheroid models for cancer initiation study. | Hakobyan D, Medina C, Dusserre N, Stachowicz ML, Handschin C, Fricain  | — | 2020 | — |
| 109 | Patient-Derived Organoids in Precision Medicine: Drug Screening, Organoid-on-a-Chip and Living Organoid Biobank. | Zhou Z, Cong L, Cong X. | — | 2021 | — |
| 110 |  | AUTHOR UNKNOWN | — | — | `10.1038/nmeth.4575` |
| 111 | Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. | Qian Y, Gong Y, Fan Z, Luo G, Huang Q, Deng S, Cheng H, Jin K, Ni Q, Y | — | 2020 | — |
| 112 | Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer. | Berger AW, Schwerdel D, Ettrich TJ, Hann A, Schmidt SA, Kleger A, Mari | — | 2017 | — |
| 113 | Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. | Herpers B, Eppink B, James MI, Cortina C, Canellas-Socias A, Boj SF, H | — | 2022 | — |

## 三、被引文献（7 条 · 引用了本文的后续工作）

| # | 标题 | 作者 | 期刊 | 年份 | PMID |
|---|---|---|---|---|---|
| 1 | An oncogenic KRAS-driven secretome involving TNFα promotes niche preparation prior to pancreatic cancer onset. | Allgöwer C, Mulaw MA, Nagai J, Wiedenmann S, Ringel EA, Ferrara B, Pie | Mol Cancer | 2026 | — |
| 2 | Multi-drug pharmacotyping improves therapy prediction in pancreatic cancer organoids. | Wansch K, Pelzer U, Schneider F, Dölvers F, Kühn A, Dragomir MP, Ihlow | Cancer Cell Int | 2025 | — |
| 3 | Pancreatic cancer patient-derived organoids capture therapy response and tumor evolution | Gout J, Perkhofer L, Lindenmayer J, Resheq YJ, Schwab JD, Kraus JM, Ro | — | 2025 | — |
| 4 | Hsa-miR-526b-5p Regulates the Sensitivity of Colorectal Cancer to 5-Fluorouracil by Targeting TP53 in Organoid Models. | Huang L, Liao C, Xiong Z, Chen Z, Zhang S. | Biochem Genet | 2026 | — |
| 5 | Splicing dysregulation: hallmark and therapeutic opportunity in pancreatic cancer. | Naro C, Ruta V, Sette C. | Trends Mol Med | 2025 | — |
| 6 | Personalized PDAC chip with functional endothelial barrier for tumour biomarker detection: A platform for precision medicine applications. | Goluba K, Parfejevs V, Rostoka E, Jekabsons K, Blake I, Neimane A, Ule | Mater Today Bio | 2024 | — |
| 7 | Landscape of human organoids: Ideal model in clinics and research. | Han X, Cai C, Deng W, Shi Y, Li L, Wang C, Zhang J, Rong M, Liu J, Fan | Innovation (Camb) | 2024 | — |

## 四、人工补齐全文的可行路径

| 路径 | 说明 |
|---|---|
| 机构订阅 | 用 Taylor & Francis 机构访问权限打开 `https://doi.org/10.1080/17460441.2023.2194627` 直接下载 PDF |
| 文献传递 | 国内高校图书馆文献传递服务提交 DOI |
| 作者索取 | 通过 Europe PMC / ResearchGate 联系通讯作者（Melzer MK, Löhr JM 等）索取 accepted manuscript |
| Semantic Scholar | S2 上可能有作者自存的 accepted manuscript 版本（PDF 键 `s2k-qHrIou6E9lP3SnkURTwW` 本轮已失效，无法自动检索） |

> 拿到 PDF 后存到 `/home/ldw/lcf_kb/papers_final/36945198.pdf`，可再补传知识库并把本文件替换为全文。