Biology subjects

Park, J.-I.

Publications and source records attributed to Park, J.-I..

9 recordsLinked to original sources

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

Modeling, dissecting, and subtyping of E-Cadherin inactivation-associated diffuse-type gastric adenocarcinoma

This study investigates diffuse-type gastric adenocarcinoma (DGAC), a deadly and treatment-resistant cancer. It reveals that CDH1 inactivation occurs in a subset of DGAC patient tumors, leading to the identification of two distinct DGAC subtypes. The findings emphasize the importance of understanding DGACs molecular diversity for personalized medicine in patients with CDH1 inactivation.

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↗

bioRxiv2023

Tumor Niche Network-Defined Subtypes Predict Immunotherapy Response of Esophageal Squamous Cell Cancer

Despite the promising outcomes of immune checkpoint blockade (ICB), resistance to ICB presents a new challenge. Therefore, selecting patients for specific ICB applications is crucial for maximizing therapeutic efficacy. Herein we curated 69 human esophageal squamous cell cancer (ESCC) patients tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC. Integrative analyses of the cellular network transcriptional signatures of T cells, myeloid cells, and fibroblasts define distinct ESCC subtypes characterized by T cell exhaustion, Interferon (IFN) a/b signaling, TIGIT enrichment, and specific marker genes. Furthermore, this approach classifies ESCC patients into ICB responders and non-responders, as validated by liquid biopsy single-cell transcriptomics. Our study stratifies ESCC patients based on TME transcriptional network, providing novel insights into tumor niche remodeling and predicting ICB responses in ESCC patients.

cancer biology↗

bioRxiv2022

Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion

Background and aimsDespite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown. MethodsUsing CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) in murine esophageal organoids (EOs). Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing (scRNA-seq). Tumorigenicity and immune evasion of organoids were monitored by allograft transplantation. Human ESCC scRNA-seq datasets were analyzed to classify patients and find subsets relevant to organoid models and immune evasion. ResultsWe established 32 genetically engineered EOs and identified key genetic determinants that drive ESCC initiation. A single-cell transcriptomic analysis uncovered that Trp53, Cdkn2a, and Notch1 (PCN) triple-knockout (KO) induces neoplastic features of ESCC by generating cell lineage heterogeneity and high cell plasticity. PCN KO also generates an immunosuppressive niche enriched with exhausted T cells and M2 macrophages via the CCL2-CCR2 axis. Mechanistically, CDKN2A inactivation transactivates CCL2 via NF-{kappa}B. Moreover, comparative single-cell transcriptomic analyses stratified ESCC patients and identified a specific subtype recapitulating the PCN-type ESCC signatures, including the high expression of CCL2 and CD274/PD-L1. ConclusionsOur study unveils that loss of TP53, CDKN2A, and NOTCH1 induces esophageal neoplasia and immune evasion for ESCC initiation and proposes the CCL2 blockade as a viable option for targeting PCN-type ESCC.

cancer biology↗

bioRxiv2022

PCLAF-DREAM Drives Alveolar Cell Plasticity for Lung Regeneration

Spatiotemporal control of stem and progenitor cells is essential for lung regeneration, the failure of which leads to lung disease. However, the mechanism of alveolar cell plasticity during regeneration remains elusive. We previously found that PCLAF remodels the DREAM complex for cell cycle re-entry. PCLAF expression is specifically enriched in proliferating lung progenitor cells, along with the DREAM target genes by lung damage. Genetic ablation of Pclaf inhibited alveolar type I (AT1) cell regeneration from alveolar type II (AT2) cells, inducing lung fibrosis. Mechanistically, the PCLAF-DREAM complex directly transactivates CLIC4, promoting TGF-{beta} signaling that regulates the balance between AT1 and AT2 cells. Furthermore, a drug candidate that mimics the PCLAF-DREAM transcriptional signatures for lung regeneration was identified and validated in organoids and mice. Our study unveils an unexpected role of the PCLAF-DREAM axis in controlling alveolar cell plasticity for lung regeneration and proposes a viable option for lung fibrosis prevention. One Sentence SummaryPCLAF-DREAM-driven alveolar cell plasticity is crucial for lung regeneration and can be pharmacologically targeted as a therapeutic strategy for lung fibrosis.

cell biology↗

bioRxiv2022

WNT5A-RHOA axis is a new vulnerability in small-cell lung cancer

WNT signaling presents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers including small-cell lung cancer (SCLC). Here we show that beta-catenin, a master mediator of canonical WNT signaling, is not required for SCLC development in genetically engineered mouse models (GEMMs) and its transcriptional program is largely silenced during tumor development. Instead, inactivation of p130 in SCLC cells induces expression of WNT5A, a ligand for beta-catenin-independent WNT pathways. WNT5A is both sufficient and required for SCLC development and cell proliferation and selectively induces Rhoa transcription and activates RHOA protein to drive SCLC. Rhoa knockout suppresses SCLC development in vivo, and chemical perturbation of RHOA selectively inhibits SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC that is distinct from other noncanonical WNT pathways. This vulnerability of p130-WNT5A-RHOA pathway provides critical insight into the development of novel therapeutic strategies for the recalcitrant cancer, as well as the stratification of patients who may benefit from them. This study also sheds new light on the heterogeneity of WNT signaling and the molecular determinants of its cell-type specificity.

cancer biology↗

bioRxiv2021

High-throughput imaging of Caenorhabditis elegans aging using collective activity monitoring

The genetic manipulability and short lifespan of C. elegans make it an important model for aging research. Widely applied methods for measurements of worm aging based on manual observation are labor intensive and low-throughput. Here, we describe the Worm Collective Activity Monitoring Platform (WormCamp), a system for assaying aging in C. elegans by monitoring activity of populations of worms in standard 24-well plates. We show that metrics based on the rate of decline in collective activity can be used to estimate the average lifespan and locomotor healthspan in the population. Using the WormCamp, we assay a panel of highly divergent natural isolates of C. elegans and show that both lifespan and locomotor healthspan display substantial heritability. To facilitate analysis of large numbers of worms, we developed a robotic imaging system capable of simultaneous automated monitoring of activity, lifespan, and locomotor healthspan in up to 2,304 populations containing a total of ~90,000 animals. We applied the automated system to conduct a large-scale RNA interference screen for genes that affect lifespan and locomotor healthspan. The WormCamp system is complementary to other current automated methods for assessing C. elegans aging and is well suited for efficiently screening large numbers of conditions.

bioengineering↗

bioRxiv2021

Yap/Taz-Activated Expansion of Tert-Expressing Acinar Cells Are Required for Pancreatic Regeneration

The expression of TERT (telomerase reverse transcriptase) has been implicated in stem and progenitor cells, which are essential for tissue homeostasis and regeneration. However, the roles of TERT-expressing cells in the pancreas remain elusive. Employing genetically engineered Tert knock-in mouse model, herein, we located a rare population of Tert+ acinar cells. While Tert+ cells are quiescent in normal conditions, acinar cell injury leads to mitotic activation of Tert+ cells and subsequent generation of new acinar cells. Moreover, the genetic ablation of Tert+ cells impairs pancreatic regeneration. We further found that Yap/Taz activation is required for the expansion of Tert+ acinar cells. Our results identified Tert+ acinar cells as a distinct subset of acinar cells, which contributes to pancreatic regeneration via Yap/Taz activation.

cell biology↗