CRACD loss induces neuroendocrine cell plasticity of lung adenocarcinoma

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, some lung adenocarcinoma (LUAD) cells transform into neuroendocrine (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD (capping protein inhibiting regulator of actin dynamics), a capping protein inhibitor, is frequently inactivated in cancers. CRACD knockout (KO) is sufficient to de-repress NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE cell plasticity is associated with cell de-differentiation and stemness-related pathway activation. The single-cell transcriptomic analysis of LUAD patient tumors recapitulates that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with impaired actin remodeling. This study reveals the crucial role of CRACD in restricting NE cell plasticity that induces cell de-differentiation of LUAD. [Display omitted] •Cracd knockout induces NE plasticity of the pulmonary epithelial cells•CRACD loss promotes NE plasticity and intratumoral heterogeneity of LUAD•CRACD-depleted cells exhibit stemness-associated characteristics•NE cells in patients’ LUAD tumors display similar features to Cracd KO LUAD Kim et al. discover that CRACD depletion induces cell plasticity, which generates neuroendocrine cells and increases tumor heterogeneity in lung adenocarcinoma.