Abstract The goal of the project was to integrate “omics” data, including genomic, epigenetic, transcriptomic and proteomic profiles, to identify a specific signature of tumor dormancy. Materials and Methods: Two murine models of tumor dormancy, B16F1 malignant melanoma and DA1-3b myeloid leukemia, were generated and exome sequencing of dormant cells and parental cells was performed.Mutations were identified. Epigenetic alterations were detected by ChIP sequencing. Briefly, repressed and activated genes were identified by sequencing DNA fragments obtained after immunoprecipitation with antibodies against H3K9 and H3K27 and against histone H3K4me3, respectively. DNA Methylation analysis was assessed by Methylation Specific PCR (MSP). Transcriptomic analysis was conducted using Agilent arrays. Proteomes were compared by mass spectrometry. For the calcium homeostasis analysis, time courses of cytosolic Ca2+ concentration were measured using the ratiometric dye Fura-2. Results: Exome analysis identified a specific gene signature of tumor dormancy in each model. Previously characterized mutations in human melanoma and myeloid leukemia were found in the murine models of B16F1 melanoma (e.g., Pten, Brca2, and CKit) and myeloid leukemia (e.g., Flt3 and Dnmt3b), thus reinforcing the relevance of these models for translational research on human pathology. ChIP sequencing revealed a specific epigenetic signature of dormant cells compared to parental cells. Global proteomic analysis showed a deregulation of proteins involved in many metabolic pathways in both models. Despite the absence of common gene mutations in the two models tested, several genes involved in calcium homeostasis were found to be mutated (Transient Receptor Potential, Store Operated calcium channels ). Regarding their epigenetic regulation assessed by MSP, no difference was observed in methylation level. Nevertheless, functional assays showed profound alterations in calcium homeostasis in the two dormant cell lines compared to the parental cell lines, suggesting a functional role of one or several receptors or ion channels in calcium signaling in tumor dormancy. Conclusions: Taken together, “omics” analyses indicate that the regulation of tumor cell dormancy is extremely complex. Therefore, an integrated approach is crucial to fully understand tumor dormancy. Bioinformatics and integrative analyses will provide a better understanding of mechanisms controlling dormancy. Finally, functional analysis of calcium homeostasis revealed a common calcium signature in dormant tumor cells compared to parental cells. The genes involved in this altered intracellular calcium flux are currently being elucidated. Citation Format: Yasmine Touil, Loïc Lemonnier, Pascaline Segard, Martin Figeac, Frédéric Leprêtre, Audrey Vincent, Lucile Noyer, Maxence Wisztorski, Jean-Pascal Gimeno, Jean-Pascal Meneboo, Guillemette Marot, Isabelle Fournier, Thierry Idziorek, Bruno Quesnel. Omics unveils a specific signature of tumor dormancy in two murine models of leukemia and melanoma [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 2671.