Chronic Obstructive Pulmonary Disease Phenotype Dictates Cancer-Promoting Stromal Gene Expression Programs

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

Research output: Contribution to journalArticle

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Abstract

RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. OBJECTIVES: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. METHODS: Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. RESULTS: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. CONCLUSIONS: Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.

Original languageEnglish (US)
Pages (from-to)S290-S291
JournalAnnals of the American Thoracic Society
Volume15
Issue number4
DOIs
StatePublished - Dec 1 2018

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Chronic Obstructive Pulmonary Disease
Phenotype
Gene Expression
Neoplasms
Lung Neoplasms
Lung
Erythroblasts
Sirolimus
Extracellular Matrix
Bone Morphogenetic Protein 1
Neoplasm Genes
Protein Biosynthesis
Proteome
Stromal Cells
Transcriptome
Interleukin-6
Carcinogenesis
Proteins
Fibroblasts

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Chronic Obstructive Pulmonary Disease Phenotype Dictates Cancer-Promoting Stromal Gene Expression Programs. / Wendt, Christine H; Sandri, Brian J; Masvidal, Laia; Murie, Carl; Bartish, Margarita; Avdulov, Svetlana V; Higgins, LeeAnn; Markowski, Todd; Peterson, Mark; Bergh, Jonas; Yang, Ping; Rolny, Charlotte; Limper, Andrew H.; Griffin, Timothy J; Bitterman, Peter B; Larsson, Ola.

In: Annals of the American Thoracic Society, Vol. 15, No. 4, 01.12.2018, p. S290-S291.

Research output: Contribution to journalArticle

Wendt, Christine H ; Sandri, Brian J ; Masvidal, Laia ; Murie, Carl ; Bartish, Margarita ; Avdulov, Svetlana V ; Higgins, LeeAnn ; Markowski, Todd ; Peterson, Mark ; Bergh, Jonas ; Yang, Ping ; Rolny, Charlotte ; Limper, Andrew H. ; Griffin, Timothy J ; Bitterman, Peter B ; Larsson, Ola. / Chronic Obstructive Pulmonary Disease Phenotype Dictates Cancer-Promoting Stromal Gene Expression Programs. In: Annals of the American Thoracic Society. 2018 ; Vol. 15, No. 4. pp. S290-S291.
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abstract = "RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. OBJECTIVES: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. METHODS: Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. RESULTS: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. CONCLUSIONS: Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.",
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AU - Wendt, Christine H

AU - Sandri, Brian J

AU - Masvidal, Laia

AU - Murie, Carl

AU - Bartish, Margarita

AU - Avdulov, Svetlana V

AU - Higgins, LeeAnn

AU - Markowski, Todd

AU - Peterson, Mark

AU - Bergh, Jonas

AU - Yang, Ping

AU - Rolny, Charlotte

AU - Limper, Andrew H.

AU - Griffin, Timothy J

AU - Bitterman, Peter B

AU - Larsson, Ola

PY - 2018/12/1

Y1 - 2018/12/1

N2 - RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. OBJECTIVES: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. METHODS: Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. RESULTS: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. CONCLUSIONS: Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.

AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that stromal cells comprising the COPD lung contain pathological gene expression programs supporting oncogenesis. OBJECTIVES: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. METHODS: Study subjects included patients with COPD with (n = 30) or without (n = 30) lung cancer across a spectrum of COPD severity. We conducted multi-omics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. RESULTS: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation impacting protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these procancer translation programs differed on the basis of COPD severity. In mild or no COPD, the mammalian target of rapamycin pathway served as an upstream driver; whereas in advanced COPD, pathways downstream of pathological extracellular matrix emerged. Both the mammalian target of rapamycin and extracellular matrix gene expression programs paralleled activation of previously identified secretomes that can be independently induced and promote cancer initiation in mouse models. These included the senescence secretome in mild to no COPD and the ETS2 (erythroblast transformation-specific 2) secretome in moderate to severe COPD. Furthermore, in situ examination of COPD lung tissue documented stromal fibroblasts expressing key cancer-associated proteins from procancer secretomes including IL-6 (senescence secretome) in mild COPD and bone morphogenetic protein-1 (ETS2 secretome) in advanced COPD. CONCLUSIONS: Two distinct stromal gene expression programs promoting cancer initiation are activated in patients with lung cancer depending on the severity of COPD as measured by lung function. Our work has implications both for screening strategies and personalized approaches to prevent cancer in COPD.

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