دورية أكاديمية
The glutathione S-transferase Gstt1 drives survival and dissemination in metastases.
العنوان: | The glutathione S-transferase Gstt1 drives survival and dissemination in metastases. |
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المؤلفون: | Ferrer CM; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. cferrer@som.umaryland.edu.; The Broad Institute of Harvard and MIT, Cambridge, MA, USA. cferrer@som.umaryland.edu.; University of Maryland School of Medicine and the Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA. cferrer@som.umaryland.edu., Cho HM; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.; The Broad Institute of Harvard and MIT, Cambridge, MA, USA., Boon R; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.; Galapagos NV, 2800 Mechelen, Belgium., Bernasocchi T; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.; The Broad Institute of Harvard and MIT, Cambridge, MA, USA., Wong LP; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA., Cetinbas M; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA., Haggerty ER; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Mitsiades I; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Wojtkiewicz GR; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA., McLoughlin DE; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.; Termeer Center for Targeted Therapies, Massachusetts General Hospital, Boston, MA, USA., Aboushousha R; University of Vermont Larner College of Medicine, Burlington, VT, USA., Abdelhamid H; University of Vermont Larner College of Medicine, Burlington, VT, USA., Kugel S; Fred Hutchison Cancer Research Center, Seattle, WA, USA., Rheinbay E; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Sadreyev R; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA., Juric D; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.; Termeer Center for Targeted Therapies, Massachusetts General Hospital, Boston, MA, USA., Janssen-Heininger YMW; University of Vermont Larner College of Medicine, Burlington, VT, USA., Mostoslavsky R; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. rmostoslavsky@mgh.harvard.edu.; The Broad Institute of Harvard and MIT, Cambridge, MA, USA. rmostoslavsky@mgh.harvard.edu. |
المصدر: | Nature cell biology [Nat Cell Biol] 2024 Jun; Vol. 26 (6), pp. 975-990. Date of Electronic Publication: 2024 Jun 11. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Macmillan Magazines Ltd Country of Publication: England NLM ID: 100890575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4679 (Electronic) Linking ISSN: 14657392 NLM ISO Abbreviation: Nat Cell Biol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : Macmillan Magazines Ltd., [1999- |
مواضيع طبية MeSH: | Glutathione Transferase*/metabolism , Glutathione Transferase*/genetics , Pancreatic Neoplasms*/pathology , Pancreatic Neoplasms*/genetics , Pancreatic Neoplasms*/enzymology , Pancreatic Neoplasms*/metabolism , Tumor Microenvironment*, Humans ; Animals ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Fibronectins/metabolism ; Neoplasm Metastasis ; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Adenocarcinoma/metabolism ; Adenocarcinoma/enzymology ; Cell Survival ; Gene Expression Regulation, Neoplastic ; Mice ; Female ; Mice, Inbred C57BL |
مستخلص: | Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1 high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1 low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment. (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.) |
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معلومات مُعتمدة: | K99 CA252600 United States CA NCI NIH HHS; R00 CA252600 United States CA NCI NIH HHS; R01CA235412 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R01GM128448 U.S. Department of Health & Human Services | National Institutes of Health (NIH) |
المشرفين على المادة: | EC 2.5.1.18 (Glutathione Transferase) EC 2.5.1.- (glutathione S-transferase T1) 0 (Fibronectins) |
تواريخ الأحداث: | Date Created: 20240611 Date Completed: 20240615 Latest Revision: 20240715 |
رمز التحديث: | 20240715 |
DOI: | 10.1038/s41556-024-01426-7 |
PMID: | 38862786 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1476-4679 |
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DOI: | 10.1038/s41556-024-01426-7 |