Abstract A15: Generation of clonal replica tumors to interrogate complexity of human cancer in vivo

• DOI: 10.1158/1538-7445.mousemodels17-a15
• Publication Date: 2018-05-15T20:05:30Z
• Authors: Sahil Seth; Chieh-Yuan Li; Denise Corti; Sara Loponte; I-Lin Ho; Edoardo Del Poggetto; Michael Peoples; Christopher Bristow; Joseph Marszalek; Timothy Heffernan; Giannicola Genovese; Giulio Draetta; Alessandro Carugo; Andrea Viale
• Keywords: Tumor Heterogeneity

Abstract Tumor evolution and adaptation, especially in response to therapy, are well-established concepts clinical oncology a major causes of treatment failure. The inability current experimental models, including genetically engineered mouse inform on the breadth functional heterogeneity within human tumors has substantially limited our understanding tumor architecture under perturbations such as pharmacologic treatments with profound negative impact cancer drug discovery research, where efficacy continues be measured terms volume. To address this technologic gap, we developed new approach based clonal tracking model vivo supporting dissection at level well study dynamics external real time. Lentivirus-based systems have been extensively used tool investigate cell heterogeneities solid tumors, but they by lack sensitivity impossibility identical clones different animals. Using revised strategy barcode patient-derived pancreatic cells coupled deep-sequencing analysis, created PDX cohorts harboring Clonal Replica Tumors (hereafter CRTs), which all mice bear maintained same clones. Because thousands common virtually identical, CRTs enable evaluation single- combined-therapy approaches mechanistic studies single can tracked extremely high precision monitor contribution even low-represented growth relapse. Since only fully appreciated upon perturbations, availability large animals bearing clonally makes critical instrument complexity vivo. Further, another advancement supported CRT platform is isolation expansion any clone interest identified through bioinformatics analysis. High-throughput characterization every population provides an invaluable identify exploitable vulnerabilities resistant In conclusion, represent innovative dissect unprecedented resolution, enabling investigation mechanisms resistance. Understanding dynamics, composition, adaptive mechanisms, how these factors may influence response, essential reach horizons care. Citation Format: Sahil Seth, Chieh-Yuan Li, Denise Corti, Sara Loponte, I-Lin Ho, Edoardo Del Poggetto, Michael Peoples, Christopher Bristow, Joseph Marszalek, Timothy Heffernan, Giannicola Genovese, Giulio Draetta, Alessandro Carugo, Andrea Viale. Generation replica interrogate [abstract]. In: Proceedings AACR Special Conference: Advances Modeling Cancer Mice: Technology, Biology, Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Res 2018;78(10 Suppl):Abstract nr A15.