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Aggressive early-stage lung adenocarcinoma is characterized by epithelial cell plasticity with acquirement of stem-like traits and immune evasion phenotype

Abstract

Lung adenocarcinoma (LUAD) is the main non-small-cell lung cancer diagnosed in ~40–50% of all lung cancer cases. Despite the improvements in early detection and personalized medicine, even a sizable fraction of patients with early-stage LUAD would experience disease relapses and adverse prognosis. Previous reports indicated the existence of LUAD molecular subtypes characterized by specific gene expression and mutational profiles, and correlating with prognosis. However, the biological and molecular features of such subtypes have not been further explored. Consequently, the mechanisms driving the emergence of aggressive LUAD remained unclear. Here, we adopted a multi-tiered approach ranging from molecular to functional characterization of LUAD and used it on multiple cohorts of patients (for a total of 1227 patients) and LUAD cell lines. We investigated the tumor transcriptome and the mutational and immune gene expression profiles, and we used LUAD cell lines for cancer cell phenotypic screening. We found that loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes, explain the aggressive behavior of a specific subset of lung adenocarcinoma that we called C1-LUAD, including early-stage disease. This subset can be identified using a 10-gene prognostic signature. Poor prognosis patients appear to have this specific molecular lung adenocarcinoma subtype which is characterized by peculiar molecular and biological features. Our data support the hypothesis that transformed lung stem/progenitor cells and/or reprogrammed epithelial cells with CSC characteristics are hallmarks of this aggressive disease. Such discoveries suggest alternative, more aggressive, therapeutic strategies for early-stage C1-LUAD.

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Fig. 1: Multi-tiered analysis of molecular features of the C1-LUAD subtype.
Fig. 2: Gene expression analysis of 1183 patients with lung adenocarcinoma.
Fig. 3: Lineage-specifying gene expression profile of C1- and nonC1-LUAD samples.
Fig. 4: Functional analysis of C1-LUAD.
Fig. 5: Mutational profile of C1- and nonC1-LUADs.
Fig. 6: Immunoprofile analysis of C1- and nonC1-LUADs.

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Acknowledgements

We are grateful to Teresa Nittoli for technical assistance and Chiara Di Giorgio for critically editing the manuscript. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Fondazione IRCCS Casa Sollievo della Sofferenza (ref. number: BIO-POLMONE – V1.0_08 Giu 16). All authors gave their consent to publication. The gene expression data used in this study are publicly available as indicated in the “Methods” and Supplementary Information sections. This work was supported by the Associazione Italiana Ricerca sul Cancro [MFAG-17568 and IG-22827 to FB; IG-20676 to EL], the Italian Ministry of Health [GR-2016-02363975 and CLEARLY to FB]. RC was supported by a fellowship from the Umberto Veronesi Foundation and the Pezcoller Foundation. TC was supported by a fellowship from the Associazione Italiana Ricerca sul Cancro (#19548) and the Umberto Veronesi Foundation.

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Conception and design: ED, VM, and FB; Development of methodology: ED, VM, FM, RC, TC, PG, and FB; Acquisition of data: ED, VM, FM, RC, TC, LC, PG, GMF, MT, and FB; Analysis and interpretation of data: ED, VM, FM, and FB; Writing, review, and/or revision of the manuscript: ED, VM, and FB; Administrative, technical, or material support: EL, MT, and PG; Study supervision: FB.

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Correspondence to Fabrizio Bianchi.

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FB has a patent US8747867B2 issued, and a patent WO2008125791A1 issued which is related to the use of the 10-gene signature described in this paper. The study funders had no role in the design of the study, the collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. Other authors declare no conflict of interest.

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Melocchi, V., Dama, E., Mazzarelli, F. et al. Aggressive early-stage lung adenocarcinoma is characterized by epithelial cell plasticity with acquirement of stem-like traits and immune evasion phenotype. Oncogene 40, 4980–4991 (2021). https://doi.org/10.1038/s41388-021-01909-z

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