Abstract B40: Lineage selective extracellular matrix interactions required for metastatic lung cancer

Abstract

Abstract Background: Lung cancers are biological heterogeneous malignancies with poor prognosis. The underlying mechanisms of this heterogeneity and their biological consequences for metastasis are poorly understood. We previously examined the molecular relationship between epithelial differentiation states, airway regeneration, lung cancer subtypes, and clinical outcome. By integrating genomics, bioinformatic, and experimental models of lung cancer metastasis, we identified a subset of metastatic lung adenocarcinoma (LUAD) defined by its expression of a novel cell lineage gene expression program (Cheung et al., Cancer Cell 2013). Results: Here we further define the molecular characteristics of this aggressive LUAD subgroup and find that it is driven by epigenetic silencing of know tumor suppressive non-coding RNAs, including mir-34a-c. This in turn activates genes encoding for specific extracellular matrix (ECM) interacting proteins. These ECM proteins include proteoglycans abundant in the inflammatory stroma of human lung cancers and lung tissue from patients with pulmonary fibrosis. Over-expressions of these proteoglycans and their corresponding cell surface receptors are defining features of recognized LUAD histotypes. In an experimental mouse model, genetic perturbations of these ECM/cell surface interactions inhibits the metastasis re-initiating capacity of LUAD cells to distant organs such as the brain. Significantly, these ECM-tumor cell interactions may also be disrupted using targeted agents currently in clinical trials. Conclusions: Our data provide a mechanistic link between the effectors of airway homeostasis, pulmonary fibrosis, and metastasis initiation by specific lung cancers. Consequently, we provide rational strategies to re-position current therapies to target the tumor microenvironment of metastatic lung adenocarcinomas. Citation Format: Don X. Nguyen. Lineage selective extracellular matrix interactions required for metastatic lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B40.