Metastasis of pancreatic cancer: An uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells
Standard
Metastasis of pancreatic cancer: An uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells. / Fabian, Alexander; Stegner, Simon; Miarka, Lauritz; Zimmermann, Johannes; Lenk, Lennart; Rahn, Sascha; Buttlar, Jann; Viol, Fabrice; Knaack, Hendrike; Esser, Daniela; Schäuble, Sascha; Großmann, Peter; Marinos, Georgios; Häsler, Robert; Mikulits, Wolfgang; Saur, Dieter; Kaleta, Christoph; Schäfer, Heiner; Sebens, Susanne.
in: CANCER LETT, Jahrgang 453, 01.07.2019, S. 95-106.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Metastasis of pancreatic cancer: An uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells
AU - Fabian, Alexander
AU - Stegner, Simon
AU - Miarka, Lauritz
AU - Zimmermann, Johannes
AU - Lenk, Lennart
AU - Rahn, Sascha
AU - Buttlar, Jann
AU - Viol, Fabrice
AU - Knaack, Hendrike
AU - Esser, Daniela
AU - Schäuble, Sascha
AU - Großmann, Peter
AU - Marinos, Georgios
AU - Häsler, Robert
AU - Mikulits, Wolfgang
AU - Saur, Dieter
AU - Kaleta, Christoph
AU - Schäfer, Heiner
AU - Sebens, Susanne
N1 - Copyright © 2019 Elsevier B.V. All rights reserved.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed when liver metastases already emerged. We recently demonstrated that hepatic stromal cells determine the dormancy status along with cancer stem cell (CSC) properties of pancreatic ductal epithelial cells (PDECs) during metastasis. This study investigated the influence of the hepatic microenvironment - and its inflammatory status - on metabolic alterations and how these impact cell growth and CSC-characteristics of PDECs. Coculture with hepatic stellate cells (HSCs), simulating a physiological liver stroma, but not with hepatic myofibroblasts (HMFs) representing liver inflammation promoted expression of Succinate Dehydrogenase subunit B (SDHB) and an oxidative metabolism along with a quiescent phenotype in PDECs. SiRNA-mediated SDHB knockdown increased cell growth and CSC-properties. Moreover, liver micrometastases of tumor bearing KPC mice strongly expressed SDHB while expression of the CSC-marker Nestin was exclusively found in macrometastases. Consistently, RNA-sequencing and in silico modeling revealed significantly altered metabolic fluxes and enhanced SDH activity predominantly in premalignant PDECs in the presence of HSC compared to HMF. Overall, these data emphasize that the hepatic microenvironment determines the metabolism of disseminated PDECs thereby controlling cell growth and CSC-properties during liver metastasis.
AB - Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed when liver metastases already emerged. We recently demonstrated that hepatic stromal cells determine the dormancy status along with cancer stem cell (CSC) properties of pancreatic ductal epithelial cells (PDECs) during metastasis. This study investigated the influence of the hepatic microenvironment - and its inflammatory status - on metabolic alterations and how these impact cell growth and CSC-characteristics of PDECs. Coculture with hepatic stellate cells (HSCs), simulating a physiological liver stroma, but not with hepatic myofibroblasts (HMFs) representing liver inflammation promoted expression of Succinate Dehydrogenase subunit B (SDHB) and an oxidative metabolism along with a quiescent phenotype in PDECs. SiRNA-mediated SDHB knockdown increased cell growth and CSC-properties. Moreover, liver micrometastases of tumor bearing KPC mice strongly expressed SDHB while expression of the CSC-marker Nestin was exclusively found in macrometastases. Consistently, RNA-sequencing and in silico modeling revealed significantly altered metabolic fluxes and enhanced SDH activity predominantly in premalignant PDECs in the presence of HSC compared to HMF. Overall, these data emphasize that the hepatic microenvironment determines the metabolism of disseminated PDECs thereby controlling cell growth and CSC-properties during liver metastasis.
U2 - 10.1016/j.canlet.2019.03.039
DO - 10.1016/j.canlet.2019.03.039
M3 - SCORING: Journal article
C2 - 30930235
VL - 453
SP - 95
EP - 106
JO - CANCER LETT
JF - CANCER LETT
SN - 0304-3835
ER -