Biology subjects

PARK, K.-S.

Publications and source records attributed to PARK, K.-S..

4 recordsLinked to original sources

bioRxiv2025

SMARCA4 is essential for early-stage tumor development but its loss promotes late-stage cancer progression in small-cell lung cancer

SMARCA4 and other components of the SWI/SNF chromatin remodeling complex have been implicated in various cancers. Yet, its role in small cell lung cancer (SCLC) tumorigenesis remains poorly understood. Genetically engineered mouse models (GEMMs) of SCLC revealed that deletion of Smarca4 significantly decreased tumor development in this model. Pharmacological inhibition of SMARCA4 decreased the proliferation of preneoplastic neuroendocrine (NE) cells. These effects coincided with reduced expression of the lineage-specific transcription factor, ASCL1, suggesting that disruption of the SMARCA4-ASCL1 axis impairs tumor development. However, Smarca4-deficient tumors, albeit smaller than controls, displayed features associated with malignant progression, including variant histology and the loss of NE differentiation. This prompted us to test the functional role of SMARCA4 in established tumor cells that recapitulate late-stage disease. Intriguingly, whilst Smarca4 knockdown in tumor cells failed to affect their proliferative capacity in vitro, Smarca4 knockdown tumors exhibited enhanced growth following subcutaneous transplantation in athymic nude mice. Interestingly, SMARCA4 knockdown significantly reduced expression and cell-surface display of PVR, a ligand for activating natural killer (NK) cells. These results led to an idea that the enhanced tumor formation was partly owing to altered tumor-NK cell interactions mediated by the SMARCA4-PVR axis in tumor cells. These findings suggest that SMARCA4 plays a temporally distinct role in SCLC, supporting early tumorigenesis but potentially functioning as a tumor suppressor in the later stages. The dramatic differences observed when targeting SMARCA4 in distinct disease states emphasize a need to acknowledge how differences in the timing of alterations can drastically alter tumor evolution.

cancer biology↗

bioRxiv2023

CRACD suppresses neuroendocrinal plasticity of lung adenocarcinoma

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, lung adenocarcinoma (LUAD) cells transform into neuroendocrinal (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD, a capping protein inhibitor, is frequently inactivated in cancers. CRACD knock-out (KO) de-represses 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 plasticity is associated with cell de-differentiation and activated stemness-related pathways. The single-cell transcriptomes of LUAD patient tumors recapitulate that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with SOX2, OCT4, and NANOG pathway activation, and impaired actin remodeling. This study reveals an unexpected role of CRACD in restricting NE cell plasticity that induces cell de-differentiation, providing new insights into cell plasticity of LUAD.

cancer biology↗

bioRxiv2023

CRACD, a gatekeeper restricting proliferation, heterogeneity, and immune evasion of small cell lung cancer

Small cell lung cancer (SCLC) is aggressive with limited therapeutic options. Despite recent advances in targeted therapies and immunotherapies, therapy resistance is a recurring issue, which might be partly due to tumor cell plasticity, a change in cell fate. Nonetheless, the mechanisms underlying tumor cell plasticity and immune evasion in SCLC remain elusive. CRACD, a capping protein inhibitor that promotes actin polymerization, is frequently inactivated in SCLC. Cracd knockout (KO) transforms preneoplastic cells into SCLC tumor-like cells and promotes in vivo SCLC development driven by Rb1, Trp53, and Rbl2 triple KO. Cracd KO induces neuroendocrine (NE) plasticity and increases tumor cell heterogeneity of SCLC tumor cells via dysregulated NOTCH1 signaling by actin cytoskeleton disruption. CRACD depletion also reduces nuclear actin and induces EZH2-mediated H3K27 methylation. This nuclear event suppresses the MHC-I genes and thereby depletes intratumoral CD8+ T cells for accelerated SCLC tumorigenesis. Pharmacological blockade of EZH2 inhibits CRACD-negative SCLC tumorigenesis by restoring MHC-I expression and immune surveillance. Unsupervised single-cell transcriptomics identifies SCLC patient tumors with concomitant inactivation of CRACD and downregulated MHC-I pathway. This study defines CRACD, an actin regulator, as a tumor suppressor that limits cell plasticity and immune evasion and proposes EZH2 blockade as a viable therapeutic option for CRACD-negative SCLC.

cancer biology↗

bioRxiv2020

Fragmentation of Small-cell Lung Cancer Regulatory States in Heterotypic Microenvironments

Small-cell lung cancers derive from pulmonary neuroendocrine cells, which have stemlike properties to reprogram into other cell types upon lung injury. It is difficult to uncouple transcriptional plasticity of these transformed cells from genetic changes that evolve in primary tumors or secondary metastases. Profiling of single cells also problematic if the required sample dissociation activates injury-like signaling and reprogramming. Here, we defined cell-state heterogeneities in situ through laser capture microdissection-based 10-cell transcriptomics coupled with stochastic-profiling fluctuation analysis. Using labeled cells from a small-cell lung cancer mouse model initiated by neuroendocrine deletion of Rb1-Trp53, we profiled variations in transcript abundance to identify cell-to-cell differences in regulatory state in vitro and in vivo. Fluctuating transcripts in spheroid culture were partly shared among Rb1-Trp53-null models, and heterogeneities increased considerably when cells were delivered intravenously to colonize the liver. Colonization of immunocompromised animals drove fractional appearance of alveolar type II-like markers and poised cells for paracrine stimulation from immune cells and hepatocytes. Immunocompetency further exaggerated the fragmentation of tumor states in the liver, yielding mixed stromal signatures evident in bulk sequencing from autochthonous tumors and metastases. Dozens of transcript heterogeneities recur irrespective of biological context; their mapped orthologs brought together observations of murine and human small-cell lung cancer. Candidate heterogeneities recurrent in the liver also stratified primary human tumors into discrete groups not readily explained by molecular subtype but with prognostic relevance. We conclude that heterotypic interactions in the liver and lung are an accelerant for intratumor heterogeneity in small-cell lung cancer. Statement of significanceThe single-cell regulatory heterogeneity of small-cell lung cancer becomes increasingly elaborate in the liver, a common metastatic site for the disease.

cancer biology↗