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

Yoojeong Seo1, Shengzhe Zhang1, Jinho Jang1

  • 1Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Biorxiv : the Preprint Server for Biology
|February 24, 2023
PubMed

Insights

Small cell lung cancer (SCLC) therapy resistance is linked to CRACD inactivation. Restoring immune surveillance via EZH2 blockade offers a new therapeutic strategy for CRACD-negative SCLC.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • Small cell lung cancer (SCLC) is aggressive with limited treatment options.
  • Therapy resistance in SCLC is a significant challenge, potentially driven by tumor cell plasticity and immune evasion.
  • The mechanisms behind SCLC plasticity and immune evasion are not fully understood.

Purpose of the Study:

  • To investigate the role of CRACD, a capping protein inhibitor, in SCLC development and progression.
  • To elucidate the mechanisms by which CRACD inactivation contributes to SCLC plasticity and immune evasion.
  • To identify potential therapeutic targets for CRACD-inactivated SCLC.

Main Methods:

  • CRACD knockout (KO) mouse models to study SCLC development.
  • Analysis of neuroendocrine (NE) plasticity and tumor cell heterogeneity.
  • Investigation of NOTCH1 signaling, actin cytoskeleton, nuclear actin, and EZH2-mediated H3K27 methylation.
  • Assessment of MHC-I gene expression and intratumoral CD8+ T cell infiltration.
  • Pharmacological blockade of EZH2 in vivo.
  • Unsupervised single-cell transcriptomics on SCLC patient tumors.

Main Results:

  • CRACD inactivation promotes SCLC development and tumor-like cell transformation.
  • CRACD KO induces NE plasticity and tumor cell heterogeneity via actin cytoskeleton disruption and NOTCH1 signaling.
  • CRACD depletion reduces nuclear actin, leading to EZH2-mediated suppression of MHC-I genes and decreased CD8+ T cells.
  • Pharmacological EZH2 blockade inhibits CRACD-negative SCLC tumorigenesis by restoring MHC-I expression and immune surveillance.
  • SCLC patient tumors with CRACD inactivation show concomitant downregulation of the MHC-I pathway.

Conclusions:

  • CRACD acts as a tumor suppressor in SCLC by limiting cell plasticity and immune evasion.
  • EZH2 blockade is a promising therapeutic strategy for CRACD-negative SCLC.
  • Understanding CRACD's role provides insights into SCLC pathogenesis and potential treatment avenues.
Keywords:
CRACDCRADEZH2KIAA1211NOTCHSmall cell lung cancercell plasticityimmune evasiontumor heterogeneity

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