Abstract 2552: Effects of liver endothelium on pancreatic cancer growth and metabolism
Authors: Zhang Wei , Wright Michel'le , Rathore Moeez , Zarei Mehrdad , Winter Jordan , Wang Rui 
Published: June 2022

Introduction: ~90% metastatic pancreatic ductal adenocarcinoma (mPDAC) are found in the liver, and 5-year survival rate for patients with mPDAC is only at 3%. Therefore, novel therapeutic strategies are urgently needed. A growing body of evidence suggest PDAC rely on mitochondrial function (oxidative phosphorylation, OXPHOS) for survival. However, PDAC liver metastases have been reported to have higher levels of glucose uptake compared to primary tumors suggesting that PDAC liver metastases may rely on glycolytic metabolism. Therefore, the relative metabolic and cellular profiles of primary and metastatic PDAC (mPDAC) remain unclear and the involved regulatory pathway(s) have not been elucidated. Our previous studies showed that liver endothelial cells (ECs) secreted soluble factors to promote the survival of colon cancer cells in a paracrine fashion. The influence of the liver EC microenvironment on mPDAC growth and metabolism has not been elucidated. In this study, we investigate the paracrine effects of liver ECs on the survival and metabolic profiles of PDAC and elucidate the involved mechanism(s).

Methods: Primary liver ECs were isolated from non-neoplastic liver. Conditioned medium (CM) from liver ECs were collected and then applied to PDAC cells, with CM from PDAC as control CM. Effects of CM on PDAC cell proliferation were measured by the MTT assay. Changes in phosphorylation of receptor tyrosine kinases (RTK) between PDAC CM and EC CM treated PADC cells were determined by a Phospho-RTK Array kit and then validated by Western blotting. Effects of EC CM on PDAC metabolism was assessed by ATP production with CellTiter-Glo and oxygen consumption rate with Agilent Seahorse Mito Stress Assay.

Results: Compared to PDAC CM, liver EC CM promoted proliferation in different PDAC cells. We found that human epidermal growth factor receptor 3 (HER3, also known asERBB3) was only expressed and activated in BxPC-3 cells (HER3+ve), in which the HER3-AKT signaling pathway was activated by EC CM. Furthermore, blocking HER3 activation with a humanized HER3 antibody, seribantumab, significantly blocked EC CM-induced AKT activation and cell proliferation. Moreover, depletion of neuregulin (NRG) from EC CM attenuated HER3-AKT activation and indicated that EC-secreted NRG might play a role in promoting PDAC growth. Furthermore, EC CM decreased the levels of ATP production and O2 consumption in PDAC cells, suggesting that EC cells reprogram PDAC metabolism away from OXPHOS mitochondrial metabolism.

Conclusions: Liver EC-secreted factors promoted PDAC growth in vitro and in vivo, and HER3 was expressed in a subset of PDAC cells and mediated EC-induced proliferation. Moreover, EC reprogramed PDAC metabolism towards glycolysis, and inhibiting the activation of HER3 shifted PDAC metabolism to OXPHOS. Our findings provide a new insight to develop new combination of HER antibody and OXPHOS inhibitor for treating patients with HER3+ve mPDAC.

Citation Format: Wei Zhang, Michel'le Wright, Moeez Rathore, Mehrdad Zarei, Jordan Winter, Rui Wang. Effects of liver endothelium on pancreatic cancer growth and metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2552.