Metastasis of pancreatic cancer: An uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells

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 -