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

Santiago Naranjo, Christina M. Cabana, Lindsay M. LaFave, Rodrigo Romero, Sean Luc Shanahan, Arjun Bhutkar, Peter M.K. Westcott, Jason M. Schenkel, Arkopravo Ghosh, Laura Z. Liao, Isabella Del Priore, Dian Yang, Tyler Jacks

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)936-949
Number of pages14
JournalGenes & development
Volume36
Issue number15-16
DOIs
StatePublished - Aug 1 2022

Keywords

  • AT2 cells
  • lung cancer
  • organoids
  • stem cells

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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