Epithelial-Myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice
Yaqing Zhang,
Wei Yan,
Esha Mathew,
Kevin T Kane,
Arthur Brannon III,
Maeva Adoumie,
Alekya Vinta,
Howard C Crawford,
Marina Pasca di Magliano
Affiliations
Yaqing Zhang
Department of Surgery, University of Michigan, Ann Arbor, United States
Wei Yan
Department of Surgery, University of Michigan, Ann Arbor, United States; Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Esha Mathew
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States
Kevin T Kane
Department of Surgery, University of Michigan, Ann Arbor, United States
Arthur Brannon III
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States; Medical Scientist Training Program, University of Michigan, Ann Arbor, United States
Maeva Adoumie
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, United States
Alekya Vinta
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, United States
Howard C Crawford
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States; Department of Internal Medicine, University of Michigan, Ann Arbor, United States; Comprehensive Cancer Center, University of Michigan, Ann Arbor, United States
Department of Surgery, University of Michigan, Ann Arbor, United States; Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States; Comprehensive Cancer Center, University of Michigan, Ann Arbor, United States; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, United States
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.
