CRACD loss induces neuroendocrine cell plasticity of lung adenocarcinoma

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number114286
JournalCell Reports
Volume43
Issue number6
DOIs
StatePublished - 25 Jun 2024

Keywords

  • ASCL1
  • cell de-differentiation
  • cell plasticity
  • CP: Cancer
  • CRACD
  • CRAD
  • KIAA1211
  • lung adenocarcinoma
  • neuroendocrine cell plasticity
  • therapy resistance
  • tumor heterogeneity

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