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LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1
Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006233/ https://www.ncbi.nlm.nih.gov/pubmed/36899005 http://dx.doi.org/10.1038/s41467-023-36824-2 |
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author | vom Stein, Alexander F. Rebollido-Rios, Rocio Lukas, Anna Koch, Maximilian von Lom, Anton Reinartz, Sebastian Bachurski, Daniel Rose, France Bozek, Katarzyna Abdallah, Ali T. Kohlhas, Viktoria Saggau, Julia Zölzer, Rebekka Zhao, Yue Bruns, Christiane Bröckelmann, Paul J. Lohneis, Philipp Büttner, Reinhard Häupl, Björn Oellerich, Thomas Nguyen, Phuong-Hien Hallek, Michael |
author_facet | vom Stein, Alexander F. Rebollido-Rios, Rocio Lukas, Anna Koch, Maximilian von Lom, Anton Reinartz, Sebastian Bachurski, Daniel Rose, France Bozek, Katarzyna Abdallah, Ali T. Kohlhas, Viktoria Saggau, Julia Zölzer, Rebekka Zhao, Yue Bruns, Christiane Bröckelmann, Paul J. Lohneis, Philipp Büttner, Reinhard Häupl, Björn Oellerich, Thomas Nguyen, Phuong-Hien Hallek, Michael |
author_sort | vom Stein, Alexander F. |
collection | PubMed |
description | Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal fibroblasts to support leukemic progression. LYN is overexpressed in fibroblasts of lymph nodes of CLL patients. LYN-deficient stromal cells reduce CLL growth in vivo. LYN-deficient fibroblasts show markedly reduced leukemia feeding capacity in vitro. Multi-omics profiling reveals that LYN regulates the polarization of fibroblasts towards an inflammatory cancer-associated phenotype through modulation of cytokine secretion and extracellular matrix composition. Mechanistically, LYN deletion reduces inflammatory signaling including reduction of c-JUN expression, which in turn augments the expression of Thrombospondin-1, which binds to CD47 thereby impairing CLL viability. Together, our findings suggest that LYN is essential for rewiring fibroblasts towards a leukemia-supportive phenotype. |
format | Online Article Text |
id | pubmed-10006233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-100062332023-03-12 LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 vom Stein, Alexander F. Rebollido-Rios, Rocio Lukas, Anna Koch, Maximilian von Lom, Anton Reinartz, Sebastian Bachurski, Daniel Rose, France Bozek, Katarzyna Abdallah, Ali T. Kohlhas, Viktoria Saggau, Julia Zölzer, Rebekka Zhao, Yue Bruns, Christiane Bröckelmann, Paul J. Lohneis, Philipp Büttner, Reinhard Häupl, Björn Oellerich, Thomas Nguyen, Phuong-Hien Hallek, Michael Nat Commun Article Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal fibroblasts to support leukemic progression. LYN is overexpressed in fibroblasts of lymph nodes of CLL patients. LYN-deficient stromal cells reduce CLL growth in vivo. LYN-deficient fibroblasts show markedly reduced leukemia feeding capacity in vitro. Multi-omics profiling reveals that LYN regulates the polarization of fibroblasts towards an inflammatory cancer-associated phenotype through modulation of cytokine secretion and extracellular matrix composition. Mechanistically, LYN deletion reduces inflammatory signaling including reduction of c-JUN expression, which in turn augments the expression of Thrombospondin-1, which binds to CD47 thereby impairing CLL viability. Together, our findings suggest that LYN is essential for rewiring fibroblasts towards a leukemia-supportive phenotype. Nature Publishing Group UK 2023-03-10 /pmc/articles/PMC10006233/ /pubmed/36899005 http://dx.doi.org/10.1038/s41467-023-36824-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article vom Stein, Alexander F. Rebollido-Rios, Rocio Lukas, Anna Koch, Maximilian von Lom, Anton Reinartz, Sebastian Bachurski, Daniel Rose, France Bozek, Katarzyna Abdallah, Ali T. Kohlhas, Viktoria Saggau, Julia Zölzer, Rebekka Zhao, Yue Bruns, Christiane Bröckelmann, Paul J. Lohneis, Philipp Büttner, Reinhard Häupl, Björn Oellerich, Thomas Nguyen, Phuong-Hien Hallek, Michael LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 |
title | LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 |
title_full | LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 |
title_fullStr | LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 |
title_full_unstemmed | LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 |
title_short | LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1 |
title_sort | lyn kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-jun and thbs1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006233/ https://www.ncbi.nlm.nih.gov/pubmed/36899005 http://dx.doi.org/10.1038/s41467-023-36824-2 |
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