Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

Mauricio S. Caetano; Maya Hassane; Hieu T. Van; Emmanuel Bugarin; Amber M. Cumpian; Christina L. McDowell; Carolina Gonzalez Cavazos; Huiyuan Zhang; Shanshan Deng; Lixia Diao; Jing Wang; Scott E. Evans; Carmen Behrens; Ignacio I. Wistuba; Susan A.W. Fuqua; Huang Lin; Laura P. Stabile; Stephanie S. Watowich; Humam Kadara; Seyed Javad Moghaddam

doi:10.1038/s41467-018-07042-y

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

Mauricio S. Caetano, Maya Hassane, Hieu T. Van, Emmanuel Bugarin, Amber M. Cumpian, Christina L. McDowell, Carolina Gonzalez Cavazos, Huiyuan Zhang, Shanshan Deng, Lixia Diao, Jing Wang, Scott E. Evans, Carmen Behrens, Ignacio I. Wistuba, Susan A.W. Fuqua, Huang Lin, Laura P. Stabile, Stephanie S. Watowich, Humam Kadara, Seyed Javad Moghaddam

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3 ^Δ/Δ ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3 ^Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3 ^Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.

Original language	English (US)
Article number	4589
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07042-y
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Bioinformatics Shared Resource
Genetically Engineered Mouse Facility
Research Animal Support Facility

Access to Document

10.1038/s41467-018-07042-y

Cite this

Caetano, M. S., Hassane, M., Van, H. T., Bugarin, E., Cumpian, A. M., McDowell, C. L., Cavazos, C. G., Zhang, H., Deng, S., Diao, L., Wang, J., Evans, S. E., Behrens, C., Wistuba, I. I., Fuqua, S. A. W., Lin, H., Stabile, L. P., Watowich, S. S., Kadara, H., & Moghaddam, S. J. (2018). Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer. Nature communications, 9(1), Article 4589. https://doi.org/10.1038/s41467-018-07042-y

Caetano, MS, Hassane, M, Van, HT, Bugarin, E, Cumpian, AM, McDowell, CL, Cavazos, CG, Zhang, H, Deng, S, Diao, L, Wang, J, Evans, SE , Behrens, C , Wistuba, II, Fuqua, SAW, Lin, H, Stabile, LP, Watowich, SS , Kadara, H & Moghaddam, SJ 2018, 'Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer', Nature communications, vol. 9, no. 1, 4589. https://doi.org/10.1038/s41467-018-07042-y

@article{3c27001389cc475a92cc5c24ab9cfee3,

title = "Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer",

abstract = " Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3 Δ/Δ ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3 Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3 Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.",

author = "Caetano, {Mauricio S.} and Maya Hassane and Van, {Hieu T.} and Emmanuel Bugarin and Cumpian, {Amber M.} and McDowell, {Christina L.} and Cavazos, {Carolina Gonzalez} and Huiyuan Zhang and Shanshan Deng and Lixia Diao and Jing Wang and Evans, {Scott E.} and Carmen Behrens and Wistuba, {Ignacio I.} and Fuqua, {Susan A.W.} and Huang Lin and Stabile, {Laura P.} and Watowich, {Stephanie S.} and Humam Kadara and Moghaddam, {Seyed Javad}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-07042-y",

language = "English (US)",

volume = "9",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

AU - Caetano, Mauricio S.

AU - Hassane, Maya

AU - Van, Hieu T.

AU - Bugarin, Emmanuel

AU - Cumpian, Amber M.

AU - McDowell, Christina L.

AU - Cavazos, Carolina Gonzalez

AU - Zhang, Huiyuan

AU - Deng, Shanshan

AU - Diao, Lixia

AU - Wang, Jing

AU - Evans, Scott E.

AU - Behrens, Carmen

AU - Wistuba, Ignacio I.

AU - Fuqua, Susan A.W.

AU - Lin, Huang

AU - Stabile, Laura P.

AU - Watowich, Stephanie S.

AU - Kadara, Humam

AU - Moghaddam, Seyed Javad

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3 Δ/Δ ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3 Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3 Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.

AB - Lung adenocarcinomas (LUADs) with mutations in the K-ras oncogene display dismal prognosis. Proinflammatory and immunomodulatory events that drive development of K-ras mutant LUAD are poorly understood. Here, we develop a lung epithelial specific K-ras mutant/Stat3 conditional knockout (LR/Stat3 Δ/Δ ) mouse model. Epithelial Stat3 deletion results in intriguing sex-associated discrepancies; K-ras mutant tumors are decreased in female LR/Stat3 Δ/Δ mice whereas tumor burdens are increased in males. RNA-sequencing and tumor microenvironment (TME) analysis demonstrate increased anti-tumor immune responses following Stat3 deletion in females and, conversely, elevated pro-tumor immune pathways in males. While IL-6 blockade in male LR/Stat3 Δ/Δ mice reduces lung tumorigenesis, inhibition of estrogen receptor signaling in female mice augments K-ras mutant oncogenesis and reprograms lung TME toward a pro-tumor phenotype. Our data underscore a critical sex-specific role for epithelial Stat3 signaling in K-ras mutant LUAD, thus paving the way for developing personalized (e.g. sex-based) immunotherapeutic strategies for this fatal disease.

UR - http://www.scopus.com/inward/record.url?scp=85056052455&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056052455&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07042-y

DO - 10.1038/s41467-018-07042-y

M3 - Article

C2 - 30389925

AN - SCOPUS:85056052455

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4589

ER -

Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this