@article{bfe9391c4f4b448486fa579fdf87f86b,
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 mass 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.",
keywords = "CAF, cancer-associated fibroblast lineages, CD105, CyTOF, Eng, mass cytometry, pancreatic cancer, tumor microenvironment, tumor-restrictive fibroblasts",
author = "Colin Hutton and Felix Heider and Adrian Blanco-Gomez and Antonia Banyard and Alexander Kononov and Xiaohong Zhang and Saadia Karim and Viola Paulus-Hock and Dale Watt and Nina Steele and Samantha Kemp and Hogg, {Elizabeth K. J.} and Joanna Kelly and Jackstadt, {Rene Filip} 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 {Pasca di Magliano}, Marina and Santiago Zelenay and Morton, {Jennifer P.} and Claus J{\o}rgensen",
note = "Funding Information: This work was supported by Cancer Research UK Institute Awards C5759/A27412 (to C.J. A.M. R.M. C.S. and S.Z.), A17196 and A21139 (to O.J.S.), and A29996 (to J.P.M.), Experimental Medicine Programme Award (A25236 to C.J. O.J.S. and J.P.M.) and European Research Council Consolidator Award (ERC-2017-COG 772577 to C.J.). A.L. received funding from ASCO Conquer Cancer Foundation Young Investigator Award and The Christie Charity. The authors would like to acknowledge colleagues at CRUK Manchester Institute Systems Oncology Team for valuable input, CRUK Manchester Institute core facilities, in particular flow cytometry, molecular biology, and visualization irradiation analysis, as well as the Biological Services Unit at the CRUK Beatson Institute. We would also like to thank William C. Hahn, Didier Trono, Inder Verma, Fernando Calvo, and Tim Somervaille for kindly sharing plasmids. Graphical abstract was created with images from BioRender.com. C.H. planned and conducted the experiments, analyzed the data, and wrote the manuscript. A.B.-G. F.H. and E.H. planned and conducted the experiments and analyzed the data. A.B. analyzed the data. A.K. conducted computational analysis. X.Z. planned and conducted the experiments. A.B. S. Karim, S. Kemp, D.W. J.K. and V.P.-H. provided technical support, conducted experiments, and provided reagents. F.H. N.S. and S. Karim, S. Kemp conducted the experiments and analyzed the data. A.L. J.V. M.P.d.M. R.-F.J. O.J.S. F.L. C.S. M.M. A.M. L.C. and R.M. provided reagents and experimental advice. S.Z. provided reagents and oversight. J.P.M. conducted the experiments, and provided reagents and oversight. C.J. conceived the project, analyzed the data, provided oversight, and wrote the manuscript. O.S. receives funding from Novartis, AstraZeneca, RedEx and Cancer Research Technology. C.J. receives funding from AstraZeneca. R.M. is an expert witness for Pfizer and, as a former employee of the Institute of Cancer Research (ICR) in London, may benefit financially from commercialized programs. C.S. and F.L. are former employees of the ICR in London and may benefit financially from commercialized programs. The other authors declare no competing interests. Funding Information: O.S. receives funding from Novartis, AstraZeneca, RedEx and Cancer Research Technology. C.J. receives funding from AstraZeneca. R.M. is an expert witness for Pfizer and, as a former employee of the Institute of Cancer Research (ICR) in London, may benefit financially from commercialized programs. C.S. and F.L. are former employees of the ICR in London and may benefit financially from commercialized programs. The other authors declare no competing interests. Funding Information: A.L. received funding from ASCO Conquer Cancer Foundation Young Investigator Award and The Christie Charity. The authors would like to acknowledge colleagues at CRUK Manchester Institute Systems Oncology Team for valuable input, CRUK Manchester Institute core facilities, in particular flow cytometry, molecular biology, and visualization irradiation analysis, as well as the Biological Services Unit at the CRUK Beatson Institute. We would also like to thank William C. Hahn, Didier Trono, Inder Verma, Fernando Calvo, and Tim Somervaille for kindly sharing plasmids. Graphical abstract was created with images from BioRender.com . Funding Information: This work was supported by Cancer Research UK Institute Awards C5759/A27412 (to C.J., A.M., R.M., C.S., and S.Z.), A17196 and A21139 (to O.J.S.), and A29996 (to J.P.M.), Experimental Medicine Programme Award ( A25236 to C.J., O.J.S., and J.P.M.) and European Research Council Consolidator Award ( ERC-2017-COG 772577 to C.J.). Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
day = "13",
doi = "10.1016/j.ccell.2021.06.017",
language = "English",
volume = "39",
pages = "1227--1244.e20",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "9",
}
