Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

Colin Hutton; Felix Heider; Adrian Blanco Gomez; Antonia Banyard; Alexander Kononov; Xiaohong Zhang; Saadia A. Karim; Viola Paulus-Hock; Dale Watt; Nina Steele; Samantha Kemp; Elizabeth Hogg; Joanna Kelly; Rene-Filip Jackstadt; Filipa Lopes; Matteo Menotti; Luke Chisholm; Angela Lamarca; Juan Valle; Owen J. Sansom; Caroline Springer; Angeliki Malliri; Richard Marais; Marina Pasca di Magliano; Santiago Zelenay; Jennifer P. Morton; Claus Jorgensen

Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

Colin Hutton, Felix Heider, Adrian Blanco Gomez, Antonia Banyard, Alexander Kononov, Xiaohong Zhang, Saadia A. Karim, Viola Paulus-Hock, Dale Watt, Nina Steele, Samantha Kemp, Elizabeth Hogg, Joanna Kelly, Rene-Filip Jackstadt, Filipa Lopes, Matteo Menotti, Luke Chisholm, Angela Lamarca, Juan Valle, Owen J. SansomCaroline Springer, Angeliki Malliri, Richard Marais, Marina Pasca di Magliano, Santiago Zelenay, Jennifer P. Morton, Claus Jorgensen

Research output: Contribution to journal › Article › peer-review

Abstract

Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mas cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105 positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105 negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.

Original language	English
Journal	Cancer Cell
Publication status	Accepted/In press - 25 Jun 2021

Embargoed Document

CANCER-CELL-D-20-00907_R4
Accepted author manuscript, 24.9 MB
Embargo ends: 1/01/31

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Hutton, C., Heider, F., Blanco Gomez, A., Banyard, A., Kononov, A., Zhang, X., Karim, S. A., Paulus-Hock, V., Watt, D., Steele, N., Kemp, S., Hogg, E., Kelly, J., Jackstadt, R.-F., Lopes, F., Menotti, M., Chisholm, L., Lamarca, A., Valle, J., ... Jorgensen, C. (Accepted/In press). Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell.

@article{60424b0cf81d496a86316374e579b02f,

title = "Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity",

abstract = "Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mas cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105 positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105 negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.",

author = "Colin Hutton and Felix Heider and {Blanco Gomez}, Adrian and Antonia Banyard and Alexander Kononov and Xiaohong Zhang and Karim, {Saadia A.} and Viola Paulus-Hock and Dale Watt and Nina Steele and Samantha Kemp and Elizabeth Hogg and Joanna Kelly and Rene-Filip Jackstadt and Filipa Lopes and Matteo Menotti and Luke Chisholm and Angela Lamarca and Juan Valle and Sansom, {Owen J.} and Caroline Springer and Angeliki Malliri and Richard Marais and {di Magliano}, {Marina Pasca} and Santiago Zelenay and Morton, {Jennifer P.} and Claus Jorgensen",

year = "2021",

month = jun,

day = "25",

language = "English",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

}

Hutton, C, Heider, F, Blanco Gomez, A, Banyard, A, Kononov, A, Zhang, X, Karim, SA, Paulus-Hock, V, Watt, D, Steele, N, Kemp, S, Hogg, E, Kelly, J, Jackstadt, R-F, Lopes, F, Menotti, M, Chisholm, L, Lamarca, A, Valle, J, Sansom, OJ, Springer, C, Malliri, A, Marais, R, di Magliano, MP, Zelenay, S, Morton, JP & Jorgensen, C 2021, 'Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity', Cancer Cell.

TY - JOUR

T1 - Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

AU - Hutton, Colin

AU - Heider, Felix

AU - Blanco Gomez, Adrian

AU - Banyard, Antonia

AU - Kononov, Alexander

AU - Zhang, Xiaohong

AU - Karim, Saadia A.

AU - Paulus-Hock, Viola

AU - Watt, Dale

AU - Steele, Nina

AU - Kemp, Samantha

AU - Hogg, Elizabeth

AU - Kelly, Joanna

AU - Jackstadt, Rene-Filip

AU - Lopes, Filipa

AU - Menotti, Matteo

AU - Chisholm, Luke

AU - Lamarca, Angela

AU - Valle, Juan

AU - Sansom, Owen J.

AU - Springer, Caroline

AU - Malliri, Angeliki

AU - Marais, Richard

AU - di Magliano, Marina Pasca

AU - Zelenay, Santiago

AU - Morton, Jennifer P.

AU - Jorgensen, Claus

PY - 2021/6/25

Y1 - 2021/6/25

N2 - Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mas cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105 positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105 negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.

AB - Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mas cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies coordinated relationships between mesenchymal and immune cell subsets in pancreatic ductal adenocarcinoma. Expression of CD105 demarks two stable and functionally distinct pancreatic fibroblast lineages, which are also identified in murine and human healthy tissues and tumors. Whereas CD105 positive pancreatic fibroblasts are permissive for tumor growth in vivo, CD105 negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.

M3 - Article

SN - 1535-6108

JO - Cancer Cell

JF - Cancer Cell

ER -

Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

Abstract

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