Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform.

Autor:	Naranjo S; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Cabana CM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., LaFave LM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Romero R; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Shanahan SL; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Bhutkar A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Westcott PMK; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Schenkel JM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.; Harvard Medical School, Boston, Massachusetts 02115, USA., Ghosh A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Liao LZ; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Del Priore I; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA., Yang D; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA., Jacks T; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2022 Aug 01; Vol. 36 (15-16), pp. 936-949. Date of Electronic Publication: 2022 Sep 29.
DOI:	10.1101/gad.349659.122
Abstrakt:	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. (© 2022 Naranjo et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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