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 - 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 -