Abstract The 18 glycosyl hydrolase gene family (GH18) contains chitinases and chitinase-like proteins (CLP) that lack enzyme activity. Chitinase 3-like-1 (Chi3l1; also called BRP-39 in mouse and YKL-40 in man), the prototypic CLP, is expressed in an exaggerated fashion in the serum and or tissues from patients with a variety of malignancies including breast, colon/rectum, ovary, melanoma, prostate, kidney, brain, bone, and lung. In many of these malignancies, there is a strong correlation between the levels of Chi3l1/YKL-40 and disease progression, prognosis and disease-free survival. However, the roles of YKL-40 in the development and progression of lung cancer has not been determined. To begin to address this issue, we generated Chi3l1/BRP-39 null mutant (Chi3l1-/-) and lung-specific overexpressing YKL-40 transgenic (YKL-40 Tg) mice and evaluated them in a number of settings. The studies demonstrated that Chi3l1/BRP-39/YKL-40 is an important regulator of cellular apoptosis, inflammation, angiogenesis and M2 macrophage differentiation. We also found that melanoma metastasis to the lung was significantly decreased in Chi3l1-/- mice and increased in YKL-40 Tg mice and that activation of the RIG-like helicase (RLH) innate immune pathway significantly decreased BRP-39 production and melanoma or breast cancer lung metastasis. Lastly, immunohistochemical (IHC) analysis demonstrated that, in mice with specific mutation of KRAS and/or p53, Chi3l1/BRP-39 is expressed in an exaggerated manner in normal peritumor tissues and lung cancer cells in early and late stages of lung cancer development, respectively. In combination, our preliminary studies demonstrate that Chi3l1/BRP-39/YKL-40 plays a critical role in the generation of a metastasis-permissive microenvironment and is dysregulated in the course of the development of primary lung cancers. Citation Format: Chun Geun Lee, Bing Ma, Ja Seok Koo, Roy S. Herbst, Jack A. Elias. Role of Chi3l1/YKL-40 in the tumor progression and metastasis in the lung. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3938. doi:10.1158/1538-7445.AM2013-3938