Loss of Parkinson's susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
| العنوان: | Loss of Parkinson's susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis |
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| المؤلفون: | Tia Dash, Katy Milne, Basile Tessier-Cloutier, Elizabeth C. Halvorsen, Nancy Erro Go, Norman S. Chow, Paalini Sathiyaseelan, Svetlana Bortnik, Nancy Dos Santos, Nicole Wretham, Maryam Osooly, Brad H. Nelson, Sharon M. Gorski, Chandra Lebovitz, Marcel B. Bally, Wan L. Lam, Shelby Thornton, Kevin L. Bennewith, Rachel A. Cederberg |
| المصدر: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Lung Neoplasms, Science, Tumor initiation, Adenocarcinoma, Cell morphology, medicine.disease_cause, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Genomic Instability, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Cancer genomics, Humans, Genetic Predisposition to Disease, Cancer models, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Lung, Cocarcinogenesis, business.industry, Smoking, Cancer, Cell Differentiation, Parkinson Disease, respiratory system, medicine.disease, LRRK2, 3. Good health, nervous system diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Carcinogens, Immunohistochemistry, Medicine, Lung cancer, Carcinogenesis, business |
| الوصف: | 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. |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d9eb95147b869b694953e678a0c93a46Test https://pubmed.ncbi.nlm.nih.gov/33483550Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d9eb95147b869b694953e678a0c93a46 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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