Actin Dysregulation Induces Neuroendocrine Plasticity and Immune Evasion: A Vulnerability of Small Cell Lung Cancer

Authors

Yoojeong Seo
Shengzhe Zhang
Jinho Jang
Kyung-Pil Ko
Kee-Beom Kim
Yuanjian Huang
Dong-Wook Kim
Bongjun Kim
Gengyi Zou
Jie Zhang
Sohee Jun
Wonhong Chu
Nicole A Kirk
Ye Eun Hwang
Young Ho Ban
Shilpa S Dhar
Joseph M Chan
Min Gyu Lee
Charles M Rudin
Kwon-Sik Park
Jae-Il Park

Language

English

Publication Date

12-6-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-67078-9

PMID

41353272

PMCID

PMC12795832

PubMedCentral® Posted Date

12-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit increased cellular heterogeneity and escape from immune surveillance. Conversely, pharmacological inhibition of EZH2 restores MHC-I expression, reactivates antitumor immunity, and suppresses tumor growth. These findings identify CRACD as a tumor suppressor that constrains cell plasticity and immune evasion, highlighting the CRACD-EZH2-MHC-I axis as a potential therapeutic vulnerability in SCLC.

Keywords

Small Cell Lung Carcinoma, Humans, Lung Neoplasms, Animals, Enhancer of Zeste Homolog 2 Protein, Actins, Cell Line, Tumor, Mice, YAP-Signaling Proteins, Signal Transduction, Adaptor Proteins, Signal Transducing, Gene Expression Regulation, Neoplastic, Immune Evasion, Transcription Factors, Cell Plasticity, CD8-Positive T-Lymphocytes, Tumor Escape, Receptors, Notch, Neuroendocrine Cells, Female, Small-cell lung cancer, Immunosurveillance

Published Open-Access

yes

Recommended Citation

Seo, Yoojeong; Zhang, Shengzhe; Jang, Jinho; et al., "Actin Dysregulation Induces Neuroendocrine Plasticity and Immune Evasion: A Vulnerability of Small Cell Lung Cancer" (2025). Faculty, Staff and Student Publications. 5538.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5538