Faculty, Staff and Student Publications

Language

English

Publication Date

2-9-2026

Journal

Cancer Cell

DOI

10.1016/j.ccell.2025.10.004

PMID

41202811

Abstract

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are prevalent in precursor lesions but become less frequent in LUADs. These niches are conserved in mice and promote alveolar progenitor growth. Targeting inflammation alone or in combination with immune checkpoint blockade in precancerous phase reduces alveolar progenitors. Epithelial-inflammatory niches are stage-specific, shape early LUAD development and represent promising targets for interception.

Keywords

Humans, Animals, Lung Neoplasms, Mice, Disease Progression, Adenocarcinoma of Lung, Inflammation, Precancerous Conditions, Stem Cell Niche, Pulmonary Alveoli, Transcriptome, Alveolar Epithelial Cells, Stem Cells, IL-1β, LUAD interception, Xenium in situ, alveolar progenitors, epithelial-immune niche, lung adenocarcinoma, lung precursor lesions, proinflammatory pathways, reactive type II pneumocytes, spatial transcriptomics

Published Open-Access

yes

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