title: miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer.
abstract: Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu.
authors.affiliation: Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University , Marburg, Germany.
authors.forename: Leonie
authors.initials: L
authors.lastname: Mühlberg
authors.affiliation: Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University , Marburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kühnemuth
authors.affiliation: Department of Surgery, University of Liverpool , Liverpool, UK.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: Department of Surgery, University of Liverpool , Liverpool, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Shaw
authors.affiliation: Institute of Pathology, University of Tuebingen , Tuebingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Institute of Microbiology, University Hospital, Philipps-University , Marburg, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Huber
authors.affiliation: Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg , Halle, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Griesmann
authors.affiliation: Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg , Halle, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Krug
authors.affiliation: Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg , Halle, Germany.
authors.forename: Marvin
authors.initials: M
authors.lastname: Schober
authors.affiliation: Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University , Marburg, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.affiliation: Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, Marburg, Germany; Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Michl
keywords: Macrophage; PDCD4; miRNA-21; pancreatic cancer; polarization