CRACD loss promotes small cell lung cancer tumorigenesis via EZH2-mediated immune evasion

Abstract

Small cell lung carcinoma (SCLC) is a lethal neuroendocrine type of lung cancer with limited therapeutic options. Despite recent advances in cancer immunotherapy, the efficacy of immunotherapy is limited to a subset of patients with SCLC. However, the mechanisms responsible for refractoriness to immunotherapy remain elusive. CRACD (capping protein inhibiting regulator of actin dynamics; KIAA1211/CRAD) is frequently mutated and transcriptionally downregulated in SCLC. Here we show that Cracd knockout (KO) enhances transformation of preneoplastic neuroendocrine cells and significantly accelerates SCLC development initiated by loss of Rb1, Trp53, and Rbl2 in the lung epithelium of mice. Cracd KO increases tumor cell heterogeneity in SCLC tumors. Notably, the Cracd-deficient SCLC tumors display exclusion of CD8+ T cells, which coincides with epigenetic suppression of the MHC-I pathway. Single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD and impairment of tumor antigen presentation. These findings define CRACD as a novel tumor suppressor that regulates the proliferation and immune recognition of SCLC cells, providing new insight into the mechanisms by which SCLC evades immune surveillance.

lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons

“…It is known that actin filament regulation is critical for neurons as it regulates growth, axon stability, and synaptic function 38 – 40 . CRACD downregulation has been strongly associated with various types of cancer and metastasis, including small cell lung carcinoma 41 , and colorectal cancer stem cells 42 . Haplotypes of CRACD have been linked to opioid use in patients, as indicated by a recent genome-wide association study (GWAS) 43 .…”