Abstract B42: Patient-derived metastatic models of pancreatic cancer: An in-vivo system for modeling metastasis and preclinical drug screening

Abstract

Abstract So far, there are few preclinical models that can recapitulate the full metastatic process of pancreatic cancer, therefore modeling of tumor progression to metastasis is urgently needed. In our laboratory, we established patient-derived cancer xenograft (PDX) metastatic models of pancreatic ductal adenocarcinoma (PDA) by orthotopic transplantation of human pancreatic tumor specimens into immunodeficient NOD/SCID/IL2λ-receptor null (NSG) mouse. Importantly, these preclinical orthotopic models preserve the histological and genetic characteristics of donor tumor and provide successful tumor growth with subsequent distal spread to the mouse liver and lung, which are the common metastatic sites of PDA patients. Furthermore, we found that in one of the PDX metastatic models, Gemcitabine and albumin-bound paclitaxel (Nab-paclitaxel) showed significant increase in survival of treated mice, compared to control group, as well as Nab-paclitaxel resulted in reducing the number of mice affected with metastasis. Currently, we are focused on identification and characterization of circulating tumor cells (CTCs) derived from PDX metastatic models, hypothesizing that CTCs population contain cells with clonal capacity to initiate distant metastases. To identify and isolate CTCs from PDX metastatic models of pancreatic cancer, we developed a magnetic separation assay using anti-human antibodies specific to the MHC-class1-surface antigens HLA-ABC, which allowed us to enumerate human tumor cells in mouse peripheral tissues. The molecular characterization of the human CTCs population at single cell level is performed via microfluidics-based platform (Fluidigm) for multiplex gene expression analysis in individual cells. This system allows us to study the simultaneous expression of groups of genes by RNAseq and resolve cellular diversity during pancreatic cancer metastasis by comparing gene expression signatures of the human tumor cells derived from orthotopic tumor, mouse metastatic organs and peripheral blood. We expect that this single cell gene expression analysis will help us to characterize the metastasis-initiating cell sub-clones within the whole heterogeneous tumor population and subsequently identify potential therapeutic targets to trigger the metastatic spread. In summary, our preclinical data provides a rationale for further use of these PDX metastatic models of pancreatic cancer for studying the molecular mechanisms involved in metastatic process, preclinical drug screening and personalized medicine strategies. Citation Format: Spas Dimitrov, Manuel Muñoz, Natalia Baños, Camino Menéndez, Victoria Bonilla, Yolanda Duran, Rodrigo Toledo, Francesca Sarno, Javier Perales-Patón, Fátima Al-Shahrour, Pedro P Lopez-Casas, Manuel Hidalgo. Patient-derived metastatic models of pancreatic cancer: An in-vivo system for modeling metastasis and preclinical drug screening. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B42.