Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice
C. Alicia Traughber,
Gauravi M. Deshpande,
Kalash Neupane,
Nilam Bhandari,
Mariam R. Khan,
Megan R. McMullen,
Shadi Swaidani,
Emmanuel Opoku,
Santoshi Muppala,
Jonathan D. Smith,
Laura E. Nagy,
Kailash Gulshan
Affiliations
C. Alicia Traughber
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Gauravi M. Deshpande
Digital Imaging Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Kalash Neupane
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Nilam Bhandari
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Mariam R. Khan
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Megan R. McMullen
Departments of Inflammation and Immunity and Gastroenterology/Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Cleveland Clinic, Cleveland, OH 44195, USA
Shadi Swaidani
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Emmanuel Opoku
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Santoshi Muppala
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Jonathan D. Smith
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Laura E. Nagy
Departments of Inflammation and Immunity and Gastroenterology/Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Northern Ohio Alcohol Center, Cleveland Clinic, Cleveland, OH 44195, USA
Kailash Gulshan
Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA; Department of Biology, Geology, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA; Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Corresponding author
Summary: The activities of the NLRP3 and AIM2 inflammasomes and Gasdermin D (GsdmD) are implicated in lung cancer pathophysiology but it’s not clear if their contributions promote or retard lung cancer progression. Using a metastatic Lewis lung carcinoma (LLC) cell model, we show that GsdmD knockout (GsdmD−/−) mice form significantly fewer cancer foci in lungs, exhibit markedly decreased lung cancer metastasis, and show a significant ∼50% increase in median survival rate. The cleaved forms of GsdmD and IL-1β were detected in lung tumor tissue, indicating inflammasome activity in lung tumor microenvironment (TME). Increased migration and growth of LLC cells was observed upon exposure to the conditioned media derived from inflammasome-induced wild type, but not the GsdmD−/−, macrophages. Using bone marrow transplantations, we show a myeloid-specific contribution of GsdmD in lung cancer metastasis. Taken together, our data show that GsdmD plays a myeloid-specific role in lung cancer progression.
