Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.

Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatory TRAF...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jennifer L Davis, Roman Thaler, Linda Cox, Biancamaria Ricci, Heather M Zannit, Fei Wan, Roberta Faccio, Amel Dudakovic, Andre J van Wijnen, Deborah J Veis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d8db811e861d4f609a79355033e728a4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d8db811e861d4f609a79355033e728a4
record_format	dspace
spelling	oai:doaj.org-article:d8db811e861d4f609a79355033e728a42021-12-02T20:06:39ZConstitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.1932-620310.1371/journal.pone.0254426https://doaj.org/article/d8db811e861d4f609a79355033e728a42021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254426https://doaj.org/toc/1932-6203Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast-Specific Protein 1 (FSP1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB immunostaining, confirming activation of alternative NF-κB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for alpha-smooth muscle actin (αSMA), although vimentin staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for cytokeratin 19 (CK19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-κB related biological processes. We conclude that constitutive activation of the alternative NF-κB pathway in the mesenchymal lineage drives spontaneous sarcoma and provides a novel mouse model for NF-κB related sarcomas.Jennifer L DavisRoman ThalerLinda CoxBiancamaria RicciHeather M ZannitFei WanRoberta FaccioAmel DudakovicAndre J van WijnenDeborah J VeisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254426 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jennifer L Davis Roman Thaler Linda Cox Biancamaria Ricci Heather M Zannit Fei Wan Roberta Faccio Amel Dudakovic Andre J van Wijnen Deborah J Veis Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.
description	Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast-Specific Protein 1 (FSP1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB immunostaining, confirming activation of alternative NF-κB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for alpha-smooth muscle actin (αSMA), although vimentin staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for cytokeratin 19 (CK19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-κB related biological processes. We conclude that constitutive activation of the alternative NF-κB pathway in the mesenchymal lineage drives spontaneous sarcoma and provides a novel mouse model for NF-κB related sarcomas.
format	article
author	Jennifer L Davis Roman Thaler Linda Cox Biancamaria Ricci Heather M Zannit Fei Wan Roberta Faccio Amel Dudakovic Andre J van Wijnen Deborah J Veis
author_facet	Jennifer L Davis Roman Thaler Linda Cox Biancamaria Ricci Heather M Zannit Fei Wan Roberta Faccio Amel Dudakovic Andre J van Wijnen Deborah J Veis
author_sort	Jennifer L Davis
title	Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.
title_short	Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.
title_full	Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.
title_fullStr	Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.
title_full_unstemmed	Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.
title_sort	constitutive activation of nf-κb inducing kinase (nik) in the mesenchymal lineage using osterix (sp7)- or fibroblast-specific protein 1 (s100a4)-cre drives spontaneous soft tissue sarcoma.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/d8db811e861d4f609a79355033e728a4
work_keys_str_mv	AT jenniferldavis constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT romanthaler constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT lindacox constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT biancamariaricci constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT heathermzannit constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT feiwan constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT robertafaccio constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT ameldudakovic constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT andrejvanwijnen constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma AT deborahjveis constitutiveactivationofnfkbinducingkinasenikinthemesenchymallineageusingosterixsp7orfibroblastspecificprotein1s100a4credrivesspontaneoussofttissuesarcoma
_version_	1718375390259445760

Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.

Ejemplares similares