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Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer
Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported....
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348714/ https://www.ncbi.nlm.nih.gov/pubmed/35867772 http://dx.doi.org/10.1371/journal.pgen.1010315 |
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author | Scales, Michael K. Velez-Delgado, Ashley Steele, Nina G. Schrader, Hannah E. Stabnick, Anna M. Yan, Wei Mercado Soto, Nayanna M. Nwosu, Zeribe C. Johnson, Craig Zhang, Yaqing Salas-Escabillas, Daniel J. Menjivar, Rosa E. Maurer, H. Carlo Crawford, Howard C. Bednar, Filip Olive, Kenneth P. Pasca di Magliano, Marina Allen, Benjamin L. |
author_facet | Scales, Michael K. Velez-Delgado, Ashley Steele, Nina G. Schrader, Hannah E. Stabnick, Anna M. Yan, Wei Mercado Soto, Nayanna M. Nwosu, Zeribe C. Johnson, Craig Zhang, Yaqing Salas-Escabillas, Daniel J. Menjivar, Rosa E. Maurer, H. Carlo Crawford, Howard C. Bednar, Filip Olive, Kenneth P. Pasca di Magliano, Marina Allen, Benjamin L. |
author_sort | Scales, Michael K. |
collection | PubMed |
description | Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression. |
format | Online Article Text |
id | pubmed-9348714 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-93487142022-08-04 Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer Scales, Michael K. Velez-Delgado, Ashley Steele, Nina G. Schrader, Hannah E. Stabnick, Anna M. Yan, Wei Mercado Soto, Nayanna M. Nwosu, Zeribe C. Johnson, Craig Zhang, Yaqing Salas-Escabillas, Daniel J. Menjivar, Rosa E. Maurer, H. Carlo Crawford, Howard C. Bednar, Filip Olive, Kenneth P. Pasca di Magliano, Marina Allen, Benjamin L. PLoS Genet Research Article Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression. Public Library of Science 2022-07-22 /pmc/articles/PMC9348714/ /pubmed/35867772 http://dx.doi.org/10.1371/journal.pgen.1010315 Text en © 2022 Scales et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Scales, Michael K. Velez-Delgado, Ashley Steele, Nina G. Schrader, Hannah E. Stabnick, Anna M. Yan, Wei Mercado Soto, Nayanna M. Nwosu, Zeribe C. Johnson, Craig Zhang, Yaqing Salas-Escabillas, Daniel J. Menjivar, Rosa E. Maurer, H. Carlo Crawford, Howard C. Bednar, Filip Olive, Kenneth P. Pasca di Magliano, Marina Allen, Benjamin L. Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer |
title | Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer |
title_full | Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer |
title_fullStr | Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer |
title_full_unstemmed | Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer |
title_short | Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer |
title_sort | combinatorial gli activity directs immune infiltration and tumor growth in pancreatic cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348714/ https://www.ncbi.nlm.nih.gov/pubmed/35867772 http://dx.doi.org/10.1371/journal.pgen.1010315 |
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