TY - JOUR
T1 - Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform
AU - Naranjo, Santiago
AU - Cabana, Christina M.
AU - LaFave, Lindsay M.
AU - Romero, Rodrigo
AU - Shanahan, Sean Luc
AU - Bhutkar, Arjun
AU - Westcott, Peter M.K.
AU - Schenkel, Jason M.
AU - Ghosh, Arkopravo
AU - Liao, Laura Z.
AU - Priore, Isabella Del
AU - Yang, Dian
AU - Jacks, Tyler
N1 - Funding Information:
We thank Carla Concepcion, Sheng Rong Ng, Tuomas Tammela, Francisco J. Sánchez-Rivera, Grissel Jaramillo, Alex Jaeger, Cateri-na Colon, Demi Sandel, William Rideout III, Kim Mercer, Megan Burger, William Freed-Pastor, and the rest of the extended Jacks laboratory family for helpful discussions and technical assistance; George Eng, Jonathan Braverman, and Omer Yilmaz for helpful advice regarding organoid culture; the Massachusetts Institute of Technology BioMicro Center for performing high-throughput sequencing; and the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center for technical support, specifically the Hope Babette Tang (1983) Histology Facility, the Flow Cytometry Core Facility, the Animal Imaging and Preclinical Testing Core, and the Peterson (1957) Nanotechnology Materials Core Facility. This work was supported by the Howard Hughes Medical Institute, the Koch Institute Support Grant (P30-CA14051) from the National Cancer Institute, and the Koch Institute Frontier Research Program through gifts from Upstage Lung Cancer. S.N. was supported by the Howard Hughes Medical Institute Gilliam Fellowship Program and the David H. Koch Graduate Fellowship Fund. S.N., C.M.C., and R.R. were supported in part by the National Institutes of Health Predoctoral Training Grant (T32GM007287). D.Y. was supported by a Damon Runyon Cancer Research Foundation Postdoctoral Fellowship (DRG-2238-18).
Funding Information:
T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific. He is also a cofounder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. He is the President of Break Through Cancer. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. T.J.’s laboratory currently also receives funding from the Johnson & Johnson Lung Cancer Initiative and the Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described here.
Publisher Copyright:
© 2022 Naranjo et al.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS, BRAF, and ALK mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.
AB - Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS, BRAF, and ALK mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.
KW - AT2 cells
KW - lung cancer
KW - organoids
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=85139570822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139570822&partnerID=8YFLogxK
U2 - 10.1101/gad.349659.122
DO - 10.1101/gad.349659.122
M3 - Article
C2 - 36175034
AN - SCOPUS:85139570822
SN - 0890-9369
VL - 36
SP - 936
EP - 949
JO - Genes and Development
JF - Genes and Development
IS - 15-16
ER -
