Cracd Loss Induces Neuroendocrine Cell Plasticity of Lung Adenocarcinoma

Authors

Bongjun Kim
Shengzhe Zhang
Yuanjian Huang
Kyung-Pil Ko
Youn-Sang Jung
Jinho Jang
Gengyi Zou
Jie Zhang
Sohee Jun
Kee-Beom Kim
Kwon-Sik Park
Jae-Il Park

Publication Date

6-25-2024

Journal

Cell Reports

Abstract

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.

Keywords

Animals, Humans, Mice, Adenocarcinoma of Lung, Cell Line, Tumor, Cell Plasticity, Gene Expression Regulation, Neoplastic, Lung Neoplasms, Neuroendocrine Cells, Microfilament Proteins

Comments

Supplementary Materials

Data Availability Statement

PMID: 38796854