Abstract Background: Liver metastasis (LM) occurs in 30% of non-small cell lung cancer patients but the contribution of the patient's genetic background to the hepatic metastasis development is unclear. Previously, we reported that inflammation contributes to the prometastatic microenvironment of the liver. Upregulation of transcriptional regulator Id1 gene has been associated with inflammation while ablation of Id1 in mice reduced inflammation. In this study Id1 deficient mice were used to analyze the role of host Id1 in the hepatic colonization of an experimental lung cancer. Methods: Lewis lung carcinoma cells were used for the experimental production of hepatic metastasis via intrasplenic injection of cancer cells in C57BL/6 wild-type and Id1-knockout (KO) mice. Animals were splenectomized to avoid flank tumor formation and weekly FDG-micro-positron emission tomographies (PET) were performed to monitor LM formation. Animals were sacrificed at the time of LM occurrence and total RNA was purified from LM. A microarray gene expression analysis (Affymetrix) with the support of Ingenuity Pathways Analysis (IPA) was performed to evaluate the potential impact of Id1 deficiency on the regulation of genes mediating cancer cell invasion and proliferation, angiogenesis and metastasis. Results: By week two after cancer cell injection, 70% wild-type and 10% Id1-KO mice had detectable hepatic metastasis by FDG-PET (p=0.02). Three weeks after injection, when 100% wild-type had LM, still just 20% Id1-KO mice had LM (p=0.015). Moreover, 50% Id1-KO mice remained LM-free >4 weeks after cancer cell injection. No other metastasis sites were detected at necropsy. A microarray gene expression analysis of LM from Id1-KO animals uncovered a remarkable downregulation (p<0.05) of specific genes involved in the activation of cancer cell proliferation (Myc, Cdc20, Smc2, Aurora kinase B, Cyclin B1, CDK1, TIMP1, Epiregulin), migration (Ccl7, Serpine1/PAI-1, VIM, Anxa2, S100A4, S100A6, Akt3, Adrenomedullin), angiogenesis (Hif1a, PGF, Nestin) and metastasis (FGFR1, Src, IL-18, MMP3, MMP12, MMP13, Amphiregulin, PDGFA, FoxM1, Hsp90AA1, MIF, Ccl2, RhoC). Conclusion: Our results demonstrate that Id1 expression deficiency impaired the metastatic process of lung cancer cells to the liver through the specific downregulation of key metastasis-associated genes and suggest that Id1-dependent mechanisms are new targets for hepatic metastasis therapeutic. This study has been partially funded by “UTE project CIMA” and an ISCIII-FIS grant 2011. Citation Format: Ignacio Gil-Bazo, Eduardo Castanon, Inés López, Victor Segura, Mariano Ponz-Sarvise, José M. López-Picazo, Maria Collantes, Margarita Ecay, Isabel Gil-Aldea, Alfonso Calvo, Fernando Vidal-Vanaclocha. Inhibitor of differentiation-1 (Id1) expression deficiency in the tumor microenvironment impairs experimental hepatic metastasis of lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1996. doi:10.1158/1538-7445.AM2014-1996