Abstract PO-131: The role of liver endothelium on pancreatic cancer growth
Authors: Zhang Wei , Wright Michel’le , Rathore Moeez , Vaziri-Gohar Ali , Winter Jordan , Wang Rui 
Published: November 2021

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among major cancers in the United States, and the 5-year survival rate for patients with metastatic PDAC (mPDAC) is only at 3%. Past studies have shown that the paracrine secretion of soluble factors by endothelial cells (ECs) created a unique niche and promoted the survival of cancer cells (cell growth or chemoresistance) in other types of cancer. The liver is the main site of distant metastases in mPDAC, but the influence of the liver EC microenvironment on mPDAC has not been elucidated. In this study, we determined the paracrine effects of liver ECs on the survival of PDAC and identify involved mechanism. Methods: Primary liver ECs were isolated from non-neoplastic liver tissues to mimic the liver EC microenvironment. 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. Involved RKTs were blocked by antibodies for determining their roles in mediating EC effects on PDAC cells. Lastly, A xenograft tumor model was used to establish PDAC tumors and then treated xenograft mice were subcutaneously injected by either PADC CM or EC CM, and tumors growth was monitored and recorded to evaluate the effect of ECs on PADCs. Results: Compared to PDAC CM, EC CM promoted proliferation in 4 different PDAC cells. We found that human epidermal growth factor receptor 3 (HER3 or ERBB3) 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, completely 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. It is interesting that ERK activation was also observed but was not affected by HER3 inhibition. It implied that EGFR signaling pathway might also be involved in EC CM induced PDAC cell growth. Moreover, the combination of cetuximab, trastuzumab and seribantumab yielded the best inhibitory ability on EC CM promoted cell growth as compared to antibody alone or the combination of two of them. Finally, EC CM promoted PDAC tumor growth was also observed in BxPC-3 derived xenograft mouse model. Conclusions: Our results demonstrated that liver EC-secreted factors promoted PDAC growth either in vitro or in vivo, and HER3 was expressed in a subset of PDAC cells and mediated EC-induced proliferation. Moreover, EGFR pathway may also play a role in EC induced cell growth and needs to be addressed in the future study. Our findings suggest a potential of using the combination of HER antibodies/inhibitors for treating patients with HER3+ve mPDACs.

Citation Format: Wei Zhang, Michel’le Wright, Moeez Rathore, Ali Vaziri-Gohar, Jordan Winter, Rui Wang. The role of liver endothelium on pancreatic cancer growth [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-131.