@article{4e017c53adc0467490dbf32e5b09ee33,
title = "Ym1+ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer",
abstract = "Desmoplasia around pancreatic lesions is a barrier for immune cells and a hallmark of developing and established pancreatic cancer. However, the contribution of the innate immune system to this process is ill-defined. Using the KC mouse model and primary cells in vitro, we show that alternatively activated macrophages (AAM) crosstalk with pancreatic lesion cells and pancreatic stellate cells (PSCs) to mediate fibrosis and progression of lesions. TGFβ1 secreted by AAM not only drives activation of quiescent PSCs but also in activated PSCs upregulates expression of TIMP1, a factor previously shown as crucial in fibrosis. Once activated, PSCs auto-stimulate proliferation via CXCL12. Furthermore, we found that TIMP1/CD63 signaling mediates PanIN lesion growth and TGFβ1 contributes to a cadherin switch and drives structural collapse of lesions, indicating a potential progression step. Taken together, our data indicate TGFβ1 produced by Ym1+ AAM as a major driver of processes that initiate the development of pancreatic cancer.",
keywords = "Cancer, Immunology, Microenvironment",
author = "{Fleming Martinez}, {Alicia K.} and D{\"o}ppler, {Heike R.} and Bastea, {Ligia I.} and Edenfield, {Brandy H.} and Liou, {Geou Yarh} and Peter Storz",
note = "Funding Information: This work was supported by NIH grant CA229560 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The graphical abstract was created with BioRender.com . All authors have no conflict of interest. We thank Dr. Yan Asmann (Associate Professor of BioMedical Informatics, Mayo Clinic) for advice on the statistical analyses, and our colleagues in the Department for Cancer Biology for helpful discussions. We also thank the Champions For Hope ( Funk-Zitiello Foundation ) and the Gary Chartrand Foundation for supporting these studies. Funding Information: This work was supported by NIH grant CA229560. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The graphical abstract was created with BioRender.com. All authors have no conflict of interest. We thank Dr. Yan Asmann (Associate Professor of BioMedical Informatics, Mayo Clinic) for advice on the statistical analyses, and our colleagues in the Department for Cancer Biology for helpful discussions. We also thank the Champions For Hope (Funk-Zitiello Foundation) and the Gary Chartrand Foundation for supporting these studies. Conceived and designed the experiments: AKFM, GYL, LIB, HRD, PS. Performed the experiments: AKFM, LIB, HRD, GYL, BHE. Analyzed the data: GYL, HRD, LIB, AKFM, PS. Wrote the paper: AKFM, PS. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = may,
day = "20",
doi = "10.1016/j.isci.2022.104327",
language = "English (US)",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "5",
}