Epithelial-Myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice
- University of Michigan, United States
Abstract
Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive carcinogenesis. Myeloid cells infiltrate the pancreas during the onset of pancreatic cancer, and promote carcinogenesis. Here, we show that the function of infiltrating myeloid cells is regulated by oncogenic Kras expressed in epithelial cells. In the presence of oncogenic Kras, myeloid cells promote acinar dedifferentiation and carcinogenesis. Upon inactivation of oncogenic Kras, myeloid cells promote re-differentiation of acinar cells, remodeling of the fibrotic stroma and tissue repair. Intriguingly, both aspects of myeloid cell activity depend, at least in part, on activation of EGFR/MAPK signaling, with different subsets of ligands and receptors in different target cells promoting carcinogenesis or repair, respectively. Thus, the cross-talk between epithelial cells and infiltrating myeloid cells determines the balance between tissue repair and carcinogenesis in the pancreas.
Article and author information
Author details
Marina Pasca di Magliano
Funding
University of Michigan (Biological Scholar Program)
- Marina Pasca di Magliano
American Cancer Society (Kras and the Inflammatory Microenvironment in Pancreatic Cancer)
- Marina Pasca di Magliano
Elsa U. Pardee Foundation (Targeting Tumor Infiltrating Immune Cells as a Therapeutic Strategy in Pancreatic Cancer)
- Marina Pasca di Magliano
National Cancer Institute (NCI-1R01CA151588)
- Marina Pasca di Magliano
National Cancer Institute (3-P30-CA-046592-28-S2)
- Marina Pasca di Magliano
National Cancer Institute (3-P30-CA-046592-28-S2)
- Howard C Crawford
National Institutes of Health (University of Michigan Program in Cellular and Molecular Biology training grant NIH T32 GM007315)
- Esha Mathew
National Institutes of Health (University of Michigan Gastrointestinal Training Grant NIH T32 DK094775)
- Esha Mathew
National Cancer Institute (P30-CA-046592)
- Marina Pasca di Magliano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PRO00005959) of the University of Michigan. The protocol was approved by the University Committee on Use and Care of Animals (UCUCA) of the University of Michigan on 11/17/2014. The current protocol is valid until 11/17/2017. For the pancreatitis experiments and tumorigenesis experiments, strict guidelines were followed to minimize suffering of the animals. Animal activity levels and weight were monitored throughout the experiments.
Copyright
© 2017, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Epithelial-Myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice
eLife 6:e27388.
https://doi.org/10.7554/eLife.27388
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