Abstract 695: Patient derived organoids model lung adenocarcinoma metastases

Abstract Introduction: While lung cancer patient-derived xenografts (PDX) models predict response to therapy, PDX tumors rarely metastasize thus offering little personalized assessment of the biology of metastases. We hypothesize that the development of an in vivo patient-derived organoid (PDO) model will improve our understanding of the underlying genomic and transcriptomic alterations that help drive the biology of metastases for specific lung adenocarcinoma (LUAD) histologic subtypes. Methods: Fresh LUAD specimens were processed and cultured using optimized organoid culture conditions. Established PDOs were characterized by histologic analyses, RNA-sequencing and whole genomic sequencing (WGS). Response to therapy of PDOs was evaluated by treatment with combined chemotherapies, targeted therapies, or co-culturing with patient-matched peripheral blood mononuclear cells (PMBC) in vitro and/or in vivo. The metastatic capabilities of PDOs were assessed in vivo using intracardiac injection and scoring for tumor outgrowth in distant organs using in vivo bioluminescence imaging system. Metastatic tumors from specific organs were isolated, PDOs reestablished, and those tumors underwent additional genomic and transcriptomic characterization. Phylogenetic analyses of tumor metastatic progression and putative metastasis markers were investigated by WGS and RNA-sequencing. Results: We successfully generated 14 PDOs from early-stage (I-II) primary LUAD specimens and 12 from human LUAD metastatic sites (brain, bone and pleural effusion). All PDOs recapitulate genetic alterations and transcriptomic signatures of their original tumors. Moreover, we found that individual PDOs exhibit distinct responses to different chemotherapy regimens and targeted therapies. Pre-treatment of PDOs with low doses of platinum-based doublet chemotherapy regimens activated patient-matched tumor specific T cells and enhanced PD-1 checkpoint inhibitor Nivolumab induced CD8+ T cell-mediated tumor killing. Importantly, utilizing our in vivo PDO metastasis model we successfully developed a platform to evaluate: 1) metastatic potential, 2) response to targeted therapies, 3) tumor evolution with respect of genomic instability, tumor phylogeny, and colonization, and 4) molecular signatures promoting tumor metastases. Conclusion: Our PDO system reliably models human LUAD in vitro and in vivo, by recapitulating histologic architectures, genomic alterations and transcriptomic signatures of the parent LUAD. Using LUAD PDOs we have successfully created multiple platforms to assess response to chemo- and targeted- therapies, develop an in vivo PDO metastasis model to assess tumor evolution, and use of patient matched PMBCs and PDOs to assess immune-priming strategies for individual patient tumors. Citation Format: Yuan Liu, David Jones. Patient derived organoids model lung adenocarcinoma metastases [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 695.