A novel murine carcinogen-induced model recapitulates the progression and heterogeneity of human lung adenocarcinoma

Aparamita Pandey; Estefany Gomez; Adriana Soto; Martín Alcaraz Jr; Shreya Jaldu; Fabiola Quezada; Camelia Dumitras; Pasquale Saggese; Bin Liu; Gregory A Fishbein; John Belperio; Steven M Dubinett; Claudio Scafoglio

doi:10.1016/j.lungcan.2025.108581

A novel murine carcinogen-induced model recapitulates the progression and heterogeneity of human lung adenocarcinoma

Lung Cancer. 2025 Aug:206:108581. doi: 10.1016/j.lungcan.2025.108581. Epub 2025 May 10.

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.
² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.
³ Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA.
⁴ Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
⁵ Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California Los Angeles, 700 Tiverton Drive, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA. Electronic address: cscafoglio@mednet.ucla.edu.

PMID: 40680437
DOI: 10.1016/j.lungcan.2025.108581

Abstract

Autochthonous murine models of lung adenocarcinoma, both genetically engineered and carcinogen-induced, show a different pattern of morphological progression when compared to human lung cancer. These models lack the accumulation of collagen in the alveolar wall and invasion of the underlying stroma, instead spreading to the air spaces as adenomas, a rare entity not associated with malignant transformation in human lungs. We developed new models of lung adenocarcinoma that more closely resemble the progression and heterogeneity of human lung cancer. These models are based on the administration of tobacco carcinogens, nicotine-derived nitrosamine ketone and benzo(a)pyrene, plus a single dose of bleomycin to induce lung fibrosis. We tested different protocols of carcinogen/bleomycin exposure in mice with lung-specific knockout of the tumor suppressor P53 induced by intranasal administration of an adenoviral vector encoding Cre recombinase. We found that these new models recapitulate more reliably the pattern of progression and the morphological heterogeneity of human lung adenocarcinoma.

Keywords: Carcinogen-induced murine models; Genetically engineered murine models; Heterogeneity; Lung adenocarcinoma; Progression.

MeSH terms

Adenocarcinoma of Lung
Adenocarcinoma* / chemically induced
Adenocarcinoma* / genetics
Adenocarcinoma* / pathology
Animals
Benzo(a)pyrene / toxicity
Carcinogens* / toxicity
Disease Models, Animal*
Disease Progression
Humans
Lung Neoplasms* / chemically induced
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Mice
Mice, Knockout
Tumor Suppressor Protein p53 / genetics

Substances

Carcinogens
Benzo(a)pyrene
Tumor Suppressor Protein p53