Abstract B32: Loss of MK2 in tumor stroma promotes aggressive tumor development in an advanced stage lung cancer model

Abstract

Abstract MAPKAP Kinase-2 (MK2) is a serine/threonine protein kinase that is activated by p38MAPK in response to a variety of stresses including DNA damage, osmotic shock, thermal injury, and inflammation/innate immune signaling downstream of TLR4 activation. MK2 controls the synthesis of many pro-inflammatory cytokines, modulates the actin cytoskeleton in stressed cells, and is responsible for maintaining both the G1/S and G2/M cell cycle checkpoints in p53-defective tumor cells after genotoxic damage. We recently created a “Cre-reversible" MK2 knock-out mouse model that allows the function of MK2 within either the tumor cells or within the tumor microenvironment to be studied independently. We found that MK2-deficient tumor cells in an MK2 wild-type stroma were dramatically sensitized to the anti-tumor effects of cisplatinum and doxorubicin (Morandell et al., Cell Reports, 2013). Here, we report that loss of MK2 in the tumor stroma with preservation of MK2 in tumor cells results in an aggressive tumor-promoting phenotype in an immuno-competent transplant K-RasG12D/p53-/- model of NSCLC. A similar tumor aggressive phenotype was observed in Tie2-Cre-driven endothelial and bone marrow-specific MK2-knockout mice compared to wild-type controls. Tumor-bearing mice with MK2-null stroma display increased total levels of MIP-1α, G-CSF, GM-CSF and IL-6 in the lung. Myeloperoxidase immunohistochemistry reveals enhanced tumor infiltration by neutrophils in these stromal MK2-deficient animals, consistent with the cytokine profile. In contrast with loss of MK2 in the stroma, direct activation of the p38MAPK/MK2 pathway in the tumor microenvironment by weekly intra-tracheal LPS exposure dramatically reduces tumor formation in an autochthonous K-RasG12D/p53-/- murine NSCLC model. Collectively, these results suggest that MK2 signaling in the endothelium and/or immune cells suppresses NSCLC tumor progression and modulates the inflammatory milieu in the tumor microenvironment. Citation Format: Ganapathy Sriram, Lucia Suarez-Lopez, Michael B. Yaffe. Loss of MK2 in tumor stroma promotes aggressive tumor development in an advanced stage lung cancer model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B32.