Distinct cancer-promoting stromal gene expression depending on lung function

Brian J. Sandri, Laia Masvidal, Carl Murie, Margarita Bartish, Svetlana Avdulov, Lee Ann Higgins, Todd Markowski, Mark Peterson, Jonas Bergh, Ping Yang, Charlotte Rolny, Andrew H. Limper, Timothy J. Griffin, Peter B. Bitterman, Chris H. Wendt, Ola Larsson

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Rationale: Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs that support oncogenesis. Objectives: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. Methods: The study included subjects with and without lung cancer across a spectrum of lung-function values. We conducted a multiomics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. Measurements and Main Results: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms that drove these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver, whereas in subjects with severe airflow obstruction, pathways downstream of pathological extracellular matrix emerged. Consistent with a role during cancer initiation, both the mTOR and extracellular matrix gene expression programs paralleled the activation of previously identified procancer secretomes. Furthermore, an in situ examination of lung tissue showed that stromal fibroblasts expressed cancer-associated proteins from two procancer secretomes: one that included IL-6 (in cases of mild or no airflow obstruction), and one that included BMP1 (in cases of severe airflow obstruction). Conclusions: Two distinct stromal gene expression programs that promote cancer initiation are activated in patients with lung cancer depending on lung function. Our work has implications both for screening strategies and for personalized approaches to cancer treatment.

Original languageEnglish (US)
Pages (from-to)348-358
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number3
DOIs
StatePublished - Aug 1 2019

Bibliographical note

Funding Information:
Supported by NHLBI grant R01-HL107612, the Swedish Research Council, the Wallenberg Academy Fellows program of the Knut and Alice Wallenberg Foundation, the Swedish Cancer Society, and the Strategic Research Program in Cancer, Karolinska Institute. This material is the result of work supported in part by resources and the use of facilities at the Veterans Affairs Medical Center, Minneapolis. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Publisher Copyright:
Copyright © 2019 by the American Thoracic Society

Keywords

  • COPD
  • Cancer
  • Fibroblast
  • Secretome
  • Translation

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