Academic Journal
Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth.
| العنوان: | Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. |
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| المؤلفون: | Bodac, A., Mayet, A., Rana, S., Pascual, J., Bowler, A.D., Roh, V., Fournier, N., Craciun, L., Demetter, P., Radtke, F., Meylan, E. |
| المصدر: | EMBO molecular medicine, vol. 16, no. 1, pp. 158-184 |
| سنة النشر: | 2024 |
| المجموعة: | Université de Lausanne (UNIL): Serval - Serveur académique lausannois |
| مصطلحات موضوعية: | Animals, Humans, Mice, Aging, Apoptosis, Apoptosis Regulatory Proteins/metabolism, bcl-X Protein, Cell Line, Tumor, Lung Neoplasms/pathology, Neutropenia/drug therapy, Neutropenia/metabolism, Neutropenia/pathology, Neutrophils/metabolism, Bcl-xL, Lung Adenocarcinoma, Mouse Models of Lung Cancer, Tumor-associated Neutrophils |
| الوصف: | Elevated peripheral blood and tumor-infiltrating neutrophils are often associated with a poor patient prognosis. However, therapeutic strategies to target these cells are difficult to implement due to the life-threatening risk of neutropenia. In a genetically engineered mouse model of lung adenocarcinoma, tumor-associated neutrophils (TAN) demonstrate tumor-supportive capacities and have a prolonged lifespan compared to circulating neutrophils. Here, we show that tumor cell-derived GM-CSF triggers the expression of the anti-apoptotic Bcl-xL protein and enhances neutrophil survival through JAK/STAT signaling. Targeting Bcl-xL activity with a specific BH3 mimetic, A-1331852, blocked the induced neutrophil survival without impacting their normal lifespan. Specifically, oral administration with A-1331852 decreased TAN survival and abundance, and reduced tumor growth without causing neutropenia. We also show that G-CSF, a drug used to combat neutropenia in patients receiving chemotherapy, increased the proportion of young TANs and augmented the anti-tumor effect resulting from Bcl-xL blockade. Finally, our human tumor data indicate the same role for Bcl-xL on pro-tumoral neutrophil survival. These results altogether provide preclinical evidence for safe neutrophil targeting based on their aberrant intra-tumor longevity. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/38177532; info:eu-repo/semantics/altIdentifier/eissn/1757-4684; info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_B146DD2E08C22; https://serval.unil.ch/notice/serval:BIB_B146DD2E08C2; https://serval.unil.ch/resource/serval:BIB_B146DD2E08C2.P001/REF.pdf |
| DOI: | 10.1038/s44321-023-00013-x |
| الاتاحة: | https://serval.unil.ch/notice/serval:BIB_B146DD2E08C2 https://doi.org/10.1038/s44321-023-00013-x https://serval.unil.ch/resource/serval:BIB_B146DD2E08C2.P001/REF.pdf http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_B146DD2E08C22 |
| Rights: | info:eu-repo/semantics/openAccess ; CC BY 4.0 ; https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.85EC1BB6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s44321-023-00013-x |
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