Traughber C Alicia, Deshpande Gauravi M, Neupane Kalash, Bhandari Nilam, Khan Mariam R, McMullen Megan R, Swaidani Shadi, Opoku Emmanuel, Muppala Santoshi, Smith Jonathan D, Nagy Laura E, Gulshan Kailash
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.
iScience. 2023 Jan 31;26(2):106076. doi: 10.1016/j.isci.2023.106076. eCollection 2023 Feb 17.
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.
NLRP3和AIM2炎性小体以及Gasdermin D（GsdmD）的活性与肺癌病理生理学有关，但尚不清楚它们的作用是促进还是阻碍肺癌进展。使用转移性Lewis肺癌（LLC）细胞模型，我们发现GsdmD基因敲除（GsdmD -/-）小鼠肺部形成的癌灶明显减少，肺癌转移显著降低，中位生存率显著提高约50%。在肺肿瘤组织中检测到GsdmD和IL -1β的裂解形式，表明肺肿瘤微环境（TME）中存在炎性小体活性。当暴露于炎性小体诱导的野生型巨噬细胞而非GsdmD -/-巨噬细胞产生的条件培养基时，观察到LLC细胞的迁移和生长增加。通过骨髓移植，我们证明了GsdmD在肺癌转移中具有髓系特异性作用。综上所述，我们的数据表明GsdmD在肺癌进展中发挥髓系特异性作用。
