Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis

Abstract Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson’s disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinic...

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Autores principales:	Chandra Lebovitz, Nicole Wretham, Maryam Osooly, Katy Milne, Tia Dash, Shelby Thornton, Basile Tessier-Cloutier, Paalini Sathiyaseelan, Svetlana Bortnik, Nancy Erro Go, Elizabeth Halvorsen, Rachel A. Cederberg, Norman Chow, Nancy Dos Santos, Kevin L. Bennewith, Brad H. Nelson, Marcel B. Bally, Wan L. Lam, Sharon M. Gorski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a628231eefc547ca89a67c8ce3fcdf31
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spelling	oai:doaj.org-article:a628231eefc547ca89a67c8ce3fcdf312021-12-02T13:51:16ZLoss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis10.1038/s41598-021-81639-02045-2322https://doaj.org/article/a628231eefc547ca89a67c8ce3fcdf312021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81639-0https://doaj.org/toc/2045-2322Abstract Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson’s disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson’s gene, promotes lung tumorigenesis.Chandra LebovitzNicole WrethamMaryam OsoolyKaty MilneTia DashShelby ThorntonBasile Tessier-CloutierPaalini SathiyaseelanSvetlana BortnikNancy Erro GoElizabeth HalvorsenRachel A. CederbergNorman ChowNancy Dos SantosKevin L. BennewithBrad H. NelsonMarcel B. BallyWan L. LamSharon M. GorskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chandra Lebovitz Nicole Wretham Maryam Osooly Katy Milne Tia Dash Shelby Thornton Basile Tessier-Cloutier Paalini Sathiyaseelan Svetlana Bortnik Nancy Erro Go Elizabeth Halvorsen Rachel A. Cederberg Norman Chow Nancy Dos Santos Kevin L. Bennewith Brad H. Nelson Marcel B. Bally Wan L. Lam Sharon M. Gorski Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
description	Abstract Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson’s disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson’s gene, promotes lung tumorigenesis.
format	article
author	Chandra Lebovitz Nicole Wretham Maryam Osooly Katy Milne Tia Dash Shelby Thornton Basile Tessier-Cloutier Paalini Sathiyaseelan Svetlana Bortnik Nancy Erro Go Elizabeth Halvorsen Rachel A. Cederberg Norman Chow Nancy Dos Santos Kevin L. Bennewith Brad H. Nelson Marcel B. Bally Wan L. Lam Sharon M. Gorski
author_facet	Chandra Lebovitz Nicole Wretham Maryam Osooly Katy Milne Tia Dash Shelby Thornton Basile Tessier-Cloutier Paalini Sathiyaseelan Svetlana Bortnik Nancy Erro Go Elizabeth Halvorsen Rachel A. Cederberg Norman Chow Nancy Dos Santos Kevin L. Bennewith Brad H. Nelson Marcel B. Bally Wan L. Lam Sharon M. Gorski
author_sort	Chandra Lebovitz
title	Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
title_short	Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
title_full	Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
title_fullStr	Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
title_full_unstemmed	Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
title_sort	loss of parkinson’s susceptibility gene lrrk2 promotes carcinogen-induced lung tumorigenesis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a628231eefc547ca89a67c8ce3fcdf31
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Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis

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