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Organoid Cultures as Preclinical Models of Non-Small Cell Lung Cancer. ​

Literature Information ​

DOI10.1158/1078-0432.CCR-19-1376
PMID31694835
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Impact Factor10.2
JCR QuartileQ1
Publication Year2020
Times Cited172
KeywordsOrganoid Culture, Non-Small Cell Lung Cancer, Drug Testing, Biomarker Validation
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN1078-0432
Pages1162-1174
Issue26(5)
AuthorsRuoshi Shi, Nikolina Radulovich, Christine Ng, Ni Liu, Hirotsugu Notsuda, Michael Cabanero, Sebastiao N Martins-Filho, Vibha Raghavan, Quan Li, Arvind Singh Mer, Joshua C Rosen, Ming Li, Yu-Hui Wang, Laura Tamblyn, Nhu-An Pham, Benjamin Haibe-Kains, Geoffrey Liu, Nadeem Moghal, Ming-Sound Tsao

TL;DR ​

This study establishes patient-derived organoid models of non-small cell lung cancer (NSCLC) that closely mimic the histology, genomic features, and tumorigenicity of primary tumors, addressing the need for relevant models to enhance drug target identification and disease understanding. The organoids retain sensitivity to targeted therapies, making them a promising platform for drug testing and biomarker validation.

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Organoid Culture · Non-Small Cell Lung Cancer · Drug Testing · Biomarker Validation

Abstract ​

PURPOSE Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease.

EXPERIMENTAL DESIGN Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment. Organoids were histologically and molecularly characterized by cytology and histology, exome sequencing, and RNA-sequencing analysis. Tumorigenicity was assessed through subcutaneous injection of organoids in NOD/SCID mice. Organoids were subjected to drug testing using EGFR, FGFR, and MEK-targeted therapies.

RESULTS We have identified cell culture conditions favoring the establishment of short-term and long-term expansion of NSCLC organoids derived from primary lung patient and PDX tumor tissue. The NSCLC organoids recapitulated the histology of the patient and PDX tumor. They also retained tumorigenicity, as evidenced by cytologic features of malignancy, xenograft formation, preservation of mutations, copy number aberrations, and gene expression profiles between the organoid and matched parental tumor tissue by whole-exome and RNA sequencing. NSCLC organoid models also preserved the sensitivity of the matched parental tumor to targeted therapeutics, and could be used to validate or discover biomarker-drug combinations.

CONCLUSIONS Our panel of NSCLC organoids closely recapitulates the genomics and biology of patient tumors, and is a potential platform for drug testing and biomarker validation.

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Primary Questions Addressed ​

  1. What specific characteristics of NSCLC organoids make them more suitable as preclinical models compared to traditional cell lines?
  2. How do the findings from organoid models influence the selection of targeted therapies for individual NSCLC patients?
  3. In what ways can the establishment of NSCLC organoids contribute to understanding the mechanisms of drug resistance in lung cancer?
  4. What are the potential limitations of using organoid cultures in modeling the heterogeneity of NSCLC tumors?
  5. How might advancements in organoid technology enhance the discovery of novel biomarkers for NSCLC treatment?

Key Findings ​

Key Insights ​

  1. Research Background and Purpose: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality globally, indicating a pressing need for effective preclinical models to facilitate drug target identification and deepen our understanding of the disease. This study aims to create and validate organoid cultures derived from NSCLC patient tissues and patient-derived xenograft (PDX) models, providing a more clinically relevant platform for research and therapeutic development.

  2. Main Methods and Findings: The researchers established organoid cultures from 30 primary NSCLC surgical resections and 35 existing PDX models. The organoids underwent rigorous histological and molecular characterization, including cytology, histology, whole-exome sequencing, and RNA sequencing. Tumorigenicity was evaluated through subcutaneous transplantation in NOD/SCID mice. The study successfully identified optimal culture conditions for both short-term and long-term expansion of NSCLC organoids, which mirrored the histological characteristics of the original tumors. Importantly, these organoids retained the genetic and phenotypic traits of their parental tumors, including mutations, copy number variations, and gene expression profiles. Furthermore, they demonstrated sensitivity to targeted therapies (EGFR, FGFR, and MEK inhibitors), confirming their functional relevance.

  3. Core Conclusions: The NSCLC organoid models established in this study closely replicate the genomic landscape and biological features of primary tumors. They preserve tumorigenicity and responsiveness to targeted treatments, making them a valuable tool for preclinical drug testing and biomarker validation. This advancement represents a significant step toward bridging the gap between laboratory research and clinical application in NSCLC.

  4. Research Significance and Impact: The development of NSCLC organoid cultures has profound implications for cancer research and treatment. These models provide a robust platform for testing therapeutic strategies and understanding tumor biology in a manner that closely reflects patient-derived characteristics. The capacity for organoids to retain key molecular features of the original tumors suggests they can serve as effective tools for personalized medicine approaches, enabling the identification of suitable biomarker-drug combinations tailored to individual patients. Ultimately, this research could accelerate the discovery of novel therapies and improve clinical outcomes for NSCLC patients.

Literatures Citing This Work ​

  1. Organoid of ovarian cancer: genomic analysis and drug screening. - H-D Liu;B-R Xia;M-Z Jin;G Lou - Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (2020)
  2. Conditional reprogramming: Modeling urological cancer and translation to clinics. - Wei Liu;Lingao Ju;Songtao Cheng;Gang Wang;Kaiyu Qian;Xuefeng Liu;Yu Xiao;Xinghuan Wang - Clinical and translational medicine (2020)
  3. Genomic characteristics and drug screening among organoids derived from non-small cell lung cancer patients. - Jing-Hua Chen;Xiang-Peng Chu;Jia-Tao Zhang;Qiang Nie;Wen-Fang Tang;Jian Su;Hong-Hong Yan;Hong-Ping Zheng;Ze-Xin Chen;Xin Chen;Meng-Meng Song;Xin Yi;Pan-Song Li;Yan-Fang Guan;Gang Li;Chu-Xia Deng;Rafael Rosell;Yi-Long Wu;Wen-Zhao Zhong - Thoracic cancer (2020)
  4. [Application of Organoids in Lung Cancer Precision Medicine]. - Ziqi Jia;Naixin Liang;Shanqing Li - Zhongguo fei ai za zhi = Chinese journal of lung cancer (2020)
  5. Human Lung Adenocarcinoma-Derived Organoid Models for Drug Screening. - Zhichao Li;Youhui Qian;Wujiao Li;Lisa Liu;Lei Yu;Xia Liu;Guodong Wu;Youyu Wang;Weibin Luo;Fuyuan Fang;Yuchen Liu;Fei Song;Zhiming Cai;Wei Chen;Weiren Huang - iScience (2020)
  6. Drug screening model meets cancer organoid technology. - Chen Liu;Tianyu Qin;Yuhan Huang;Yuan Li;Gang Chen;Chaoyang Sun - Translational oncology (2020)
  7. Engineered tissues and strategies to overcome challenges in drug development. - Andrew S Khalil;Rudolf Jaenisch;David J Mooney - Advanced drug delivery reviews (2020)
  8. Patient-derived cell line, xenograft and organoid models in lung cancer therapy. - Ku-Geng Huo;Elisa D'Arcangelo;Ming-Sound Tsao - Translational lung cancer research (2020)
  9. Lung organoids: advances in generation and 3D-visualization. - Brian Cunniff;Joseph E Druso;Jos L van der Velden - Histochemistry and cell biology (2021)
  10. Future perspectives from lung cancer pre-clinical models: new treatments are coming? - Francesca Bersani;Deborah Morena;Francesca Picca;Alessandro Morotti;Fabrizio Tabbò;Paolo Bironzo;Luisella Righi;Riccardo Taulli - Translational lung cancer research (2020)

... (162 more literatures)

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