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Published on: September 15, 2023
Organoid Cultures as Preclinical Models of Non-Small Cell Lung Cancer
Ruoshi Shi1,2, Nikolina Radulovich1, Christine Ng1
1University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
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.
Insights
Researchers developed new non-small cell lung cancer (NSCLC) organoid models from patient tumors. These models accurately reflect tumor biology and are useful for drug testing and biomarker discovery in NSCLC.
Area of Science:
- Oncology
- Cancer Biology
- Drug Discovery
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality globally.
- There is a critical need for advanced preclinical models to study NSCLC and identify new therapeutic targets.
Purpose of the Study:
- To establish and characterize novel organoid models from NSCLC patient tumors and patient-derived xenografts (PDX).
- To evaluate the utility of these organoid models for drug sensitivity testing and biomarker validation.
Main Methods:
- Organoid cultures were established from 30 primary NSCLC patient tissues and 35 PDX models.
- Characterization involved histological, cytological, whole-exome sequencing, and RNA-sequencing analyses.
- Tumorigenicity was confirmed via xenograft formation in mice, and drug sensitivity was tested using targeted therapies.
Main Results:
- Successfully established short-term and long-term NSCLC organoid cultures that recapitulated patient tumor histology.
- Organoids maintained tumorigenicity and genetic fidelity (mutations, copy number aberrations, gene expression) compared to parental tumors.
- NSCLC organoid models demonstrated preserved sensitivity to targeted therapies, mirroring patient tumor responses.
Conclusions:
- A panel of NSCLC organoids was developed that closely mimics the genomics and biology of patient tumors.
- These organoid models represent a valuable platform for preclinical drug testing and the validation of predictive biomarkers in NSCLC.
