TY - JOUR
T1 - Organoid cultures as preclinical models of non-small cell lung cancer
AU - Shi, Ruoshi
AU - Radulovich, Nikolina
AU - Ng, Christine
AU - Liu, Ni
AU - Notsuda, Hirotsugu
AU - Cabanero, Michael
AU - Martins-Filho, Sebastiao N.
AU - Raghavan, Vibha
AU - Li, Quan
AU - Mer, Arvind Singh
AU - Rosen, Joshua C.
AU - Li, Ming
AU - Wang, Yu Hui
AU - Tamblyn, Laura
AU - Pham, Nhu An
AU - Haibe-Kains, Benjamin
AU - Liu, Geoffrey
AU - Moghal, Nadeem
AU - Tsao, Ming Sound
N1 - Funding Information:
G. Liu is a paid consultant for AstraZeneca, Takeda, Pfizer, Novartis, Roche, Bristol-Myers Squibb, Bayer, and EMD Serono, and reports receiving commercial research grants from Takeda, AstraZeneca, and Boehringer Ingelheim. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was supported by Canadian Institute of Health Research (CIHR) Foundation grant FDN-148395 (to M.-S. Tsao), Canadian Cancer Society Research Institute IMPACT grants 701595 (to M.-S. Tsao) and 703206 (to G. Liu), and the Princess Margaret Cancer Foundation (for PM Living Biobank core). R. Shi is funded by a University of Toronto Ontario Student Opportunity Trust Fund (OSOTF) and Ontario Graduate Scholarship (OGS). M. Cabanero was supported by the Terry Fox Foundation Training Program in Molecular Pathology of Cancer at CIHR (STP 53912). S.N. Martins-Filho was supported by a Training Program grant from the
Funding Information:
This work was supported by Canadian Institute of Health Research (CIHR) Foundation grant FDN-148395 (to M.-S. Tsao), Canadian Cancer Society Research Institute IMPACT grants 701595 (to M.-S. Tsao) and 703206 (to G. Liu), and the Princess Margaret Cancer Foundation (for PM Living Biobank core). R. Shi is funded by a University of Toronto Ontario Student Opportunity Trust Fund (OSOTF) and Ontario Graduate Scholarship (OGS). M. Cabanero was supported by the Terry Fox Foundation Training Program in Molecular Pathology of Cancer at CIHR (STP 53912). S.N. Martins-Filho was supported by a Training Program grant from the Terry Fox Research Institute and Princess Margaret Cancer Foundation. G. Liu is the Alan B. Brown Chair in Molecular Genomics. M.-S. Tsao is the M. Qasim Choksi Chair in Lung Cancer Translational Research. The authors thank Jing Xu, Wendy So, and Jian Zhou for all IHC staining. They acknowledge the Princess Margaret Biobank for providing patient tissue samples. They thank the Princess Margaret Genomics Centre (PMGC), especially Julissa Tsao, for exome sequencing RNA sequencing. They thank Drs. Trevor Pugh and Vuk Stambolic for advice and guidance of the project.
Publisher Copyright:
© 2020 American Association for Cancer Research Inc.. All rights reserved.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-19-1376
DO - 10.1158/1078-0432.CCR-19-1376
M3 - Article
C2 - 31694835
AN - SCOPUS:85081285170
VL - 26
SP - 1162
EP - 1174
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 5
ER -