Cargando…

Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma

BACKGROUND & AIMS: Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneou...

Descripción completa

Detalles Bibliográficos
Autores principales: Garcia, Paloma E., Adoumie, Maeva, Kim, Esther C., Zhang, Yaqing, Scales, Michael K., El-Tawil, Yara S., Shaikh, Amara Z., Wen, Hui-Ju, Bednar, Filip, Allen, Ben L., Wellik, Deneen M., Crawford, Howard C., Pasca di Magliano, Marina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399194/
https://www.ncbi.nlm.nih.gov/pubmed/32454112
http://dx.doi.org/10.1016/j.jcmgh.2020.05.004
_version_ 1783566104056037376
author Garcia, Paloma E.
Adoumie, Maeva
Kim, Esther C.
Zhang, Yaqing
Scales, Michael K.
El-Tawil, Yara S.
Shaikh, Amara Z.
Wen, Hui-Ju
Bednar, Filip
Allen, Ben L.
Wellik, Deneen M.
Crawford, Howard C.
Pasca di Magliano, Marina
author_facet Garcia, Paloma E.
Adoumie, Maeva
Kim, Esther C.
Zhang, Yaqing
Scales, Michael K.
El-Tawil, Yara S.
Shaikh, Amara Z.
Wen, Hui-Ju
Bednar, Filip
Allen, Ben L.
Wellik, Deneen M.
Crawford, Howard C.
Pasca di Magliano, Marina
author_sort Garcia, Paloma E.
collection PubMed
description BACKGROUND & AIMS: Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis. METHODS: We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1(+) or Hoxb6(+) fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis. RESULTS: Although in the healthy pancreas Gli1(+) fibroblasts and Hoxb6(+) fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1(+) fibroblasts expand dramatically, whereas Hoxb6(+) cells do not. CONCLUSIONS: Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1(+) and Hoxb6(+) fibroblasts and found only Gli1(+) expanded to contribute to the stroma during pancreatic carcinogenesis.
format Online
Article
Text
id pubmed-7399194
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-73991942020-08-06 Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma Garcia, Paloma E. Adoumie, Maeva Kim, Esther C. Zhang, Yaqing Scales, Michael K. El-Tawil, Yara S. Shaikh, Amara Z. Wen, Hui-Ju Bednar, Filip Allen, Ben L. Wellik, Deneen M. Crawford, Howard C. Pasca di Magliano, Marina Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Although the healthy pancreas consists mostly of epithelial cells, pancreatic cancer and the precursor lesions known as pancreatic intraepithelial neoplasia, are characterized by an extensive accumulation of fibroinflammatory stroma that includes a substantial and heterogeneous fibroblast population. The cellular origin of fibroblasts within the stroma has not been determined. Here, we show that the Gli1 and Hoxb6 markers label distinct fibroblast populations in the healthy mouse pancreas. We then set out to determine whether these distinct fibroblast populations expanded during carcinogenesis. METHODS: We developed genetically engineered models using a dual-recombinase approach that allowed us to induce pancreatic cancer formation through codon-optimized Flp recombinase-driven epithelial recombination of Kirsten rat sarcoma viral oncogene homolog while labeling Gli1(+) or Hoxb6(+) fibroblasts in an inducible manner. By using these models, we lineage-traced these 2 fibroblast populations during the process of carcinogenesis. RESULTS: Although in the healthy pancreas Gli1(+) fibroblasts and Hoxb6(+) fibroblasts are present in similar numbers, they contribute differently to the stroma in carcinogenesis. Namely, Gli1(+) fibroblasts expand dramatically, whereas Hoxb6(+) cells do not. CONCLUSIONS: Fibroblasts present in the healthy pancreas expand during carcinogenesis, but with a different prevalence for different subtypes. Here, we compared Gli1(+) and Hoxb6(+) fibroblasts and found only Gli1(+) expanded to contribute to the stroma during pancreatic carcinogenesis. Elsevier 2020-05-23 /pmc/articles/PMC7399194/ /pubmed/32454112 http://dx.doi.org/10.1016/j.jcmgh.2020.05.004 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Garcia, Paloma E.
Adoumie, Maeva
Kim, Esther C.
Zhang, Yaqing
Scales, Michael K.
El-Tawil, Yara S.
Shaikh, Amara Z.
Wen, Hui-Ju
Bednar, Filip
Allen, Ben L.
Wellik, Deneen M.
Crawford, Howard C.
Pasca di Magliano, Marina
Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma
title Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma
title_full Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma
title_fullStr Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma
title_full_unstemmed Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma
title_short Differential Contribution of Pancreatic Fibroblast Subsets to the Pancreatic Cancer Stroma
title_sort differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399194/
https://www.ncbi.nlm.nih.gov/pubmed/32454112
http://dx.doi.org/10.1016/j.jcmgh.2020.05.004
work_keys_str_mv AT garciapalomae differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT adoumiemaeva differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT kimestherc differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT zhangyaqing differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT scalesmichaelk differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT eltawilyaras differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT shaikhamaraz differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT wenhuiju differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT bednarfilip differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT allenbenl differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT wellikdeneenm differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT crawfordhowardc differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma
AT pascadimaglianomarina differentialcontributionofpancreaticfibroblastsubsetstothepancreaticcancerstroma