Abstract 1911: Bi-directional cross-talk of pancreatic cancer and stellate cells, mediated through CXCR4 and hedgehog pathways, promotes chemoresistance via its effect on gemcitabine metabolism, ROS detoxification and cancer stemness

Abstract

Abstract Mounting evidence suggests that tumor-stromal interactions play a key role in pancreatic cancer (PC) pathogenesis and chemoresistance. We previously demonstrated that CXCL12, a chemokine secreted by activated pancreatic stellate cells (PSCs), promoted PC chemoresistance upon binding to its receptor CXCR4. Furthermore, activation of CXCL12/CXCR4 pathway in PC cells (PCCs) also increased the expression and secretion of sonic hedgehog (SHH), which is a known inducer of PSCs thus establishing a bi-directional tumor-stromal crosstalk. Here we present data to support that dual targeting of CXCL12/CXCR4 and hedgehog pathways is effective in improving therapeutic outcome in PC by diminishing multiple chemoresistance mechanisms. Monoculture of PCCs (MiaPaCa and Colo357) or coculture of PCCs and PSCs were treated with gemcitabine in the presence and absence of CXCR4 antagonist (AMD3100) and hedgehog inhibitor (GDC-0449). The data demonstrated that PCCs in coculture had better survival against gemcitabine treatment as compared to those grown in monoculture and inhibition of CXCL12/CXCR4 and hedgehog pathways abrogated this co-culture-induced chemoresistance. In further mechanistic studies, we identified co-culture-induced changes in gene expression and confirmed their functional significance in chemoresistance. Our data established important roles of genes associated with gemcitabine metabolism, ROS detoxification and stemness in PC chemoresistance. Inhibition of CXCL12/CXCR4 and hedgehog pathways led to increase in gemcitabine-mediated ROS production, enhanced accumulation of active gemcitabine metabolite (gemcitabine tri-phosphate) and reduced stemness in cocultured PCCs. Finally, we examined the efficacy of our dual targeting approach in vivo in an orthotopic mouse model of pancreatic cancer by treating the mice with gemcitabine alone or in combination with AMD3100 and/or GDC-0449. Our data demonstrated that mice treated with gemcitabine along with AMD3100 and/or GDC-0449 had significantly greater reduction in tumor growth as compared to those treated with gemcitabine only. Studies are ongoing in additional pancreatic tumor models. Together, these findings provide strong evidence in support of a novel combination therapy for pancreatic cancer treatment. Citation Format: Mohammad Aslam Khan, Girijesh K. Patel, Sanjeev K. Srivastava, Sumit Arora, Haseeb Zubair, James Elliot Carter, Bin Wang, Seema Singh, Moh’d Khushman, Ajay P. Singh. Bi-directional cross-talk of pancreatic cancer and stellate cells, mediated through CXCR4 and hedgehog pathways, promotes chemoresistance via its effect on gemcitabine metabolism, ROS detoxification and cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1911.