Biology subjects

Kim, I. Y.

Publications and source records attributed to Kim, I. Y..

7 recordsLinked to original sources

bioRxiv2025

Graded Notch Signaling Functions as a Rheostat of Lineage Plasticity and Therapy Resistance in Prostate Cancer

Resistance to androgen receptor (AR)-targeted therapies such as enzalutamide in castration-resistant prostate cancer (CRPC) often arises through lineage plasticity, yet the molecular mechanisms that define this process remain incompletely understood. While previous studies reported that Notch1 and Notch2 exert distinct and sometimes opposing effects in prostate cancer differentiation, the integrated role of Notch pathway activity has not been systematically explored. Here, we identify Notch signaling as a graded Rheostat that governs prostate cancer cell fate transitions. Integrative transcriptomic and functional analyses revealed that intermediate Notch activity maintains a stem-like progenitor state, whereas reduced or elevated signaling drives divergent differentiation trajectories toward luminal or neuroendocrine lineages, respectively. During CRPC progression and enzalutamide resistance, Notch signaling becomes dynamically rewired, peaking in progenitor-like populations that sustain plasticity and survival. Both CRISPR-mediated knockout and pharmacologic inhibition of Notch signaling depleted these progenitor cells and restored enzalutamide sensitivity. These findings demonstrate that the level, rather than the binary presence, of Notch signaling dictates lineage directionality and therapeutic response in CRPC, establishing it as a tunable and actionable driver of resistance.

cancer biology↗

bioRxiv2025

RUNX1T1-HDAC Reprogramming of the HOX Code Signaling Drives a Targetable Pan-Cancer Lineage Plasticity

Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of pan-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, in specific lineages. By analyzing multi-omics data, including 39 HOX genes from over 80,000 RNA-seq samples across 114 cancer types, we discovered that HOX code expression robustly represents cancer cell lineages and reveals multiple previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying altered HOX patterns compared to non-plastic subtypes. Differential analysis further identified RUNX1T1 as a novel and consistent marker of plasticity, elevated across all three cancer types and correlating with HOX code and lineage-plastic marker genes. We validated these correlations in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and provided direct functional evidence that RUNX1T1 is required for lineage-plastic programs in prostate cancer. Using AI-based modeling, we identified NCOR/HDAC as RUNX1T1 binding partners forming a co-repressor complex that regulates HOX codes and plasticity. Finally, pharmacologic HDAC inhibition selectively suppressed the growth of plastic cells, revealing a novel therapeutic vulnerability. These findings establish ectopic RUNX1T1 as a pan-cancer biomarker and critical mediator of lineage plasticity and identify the RUNX1T1-HDAC complex as a druggable target.

cancer biology↗

bioRxiv2025

Notch as a Driver of Lineage Plasticity and Therapeutic Target in Enzalutamide-Resistant Prostate Cancer

Resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, in castration-resistant prostate cancer (CRPC) remains a significant clinical challenge, often driven by mechanisms including lineage plasticity. The precise molecular mechanisms driving this process, particularly downstream effectors, remain incompletely understood. Given its established roles in cell fate and stemness, alongside its complex functions in prostate cancer, the Notch signaling pathway presented a compelling focus for study. This study investigates the role of Notch signaling in mediating lineage plasticity and therapeutic resistance in CRPC. Employing transcriptomic analysis and functional assays, we identified Notch activity is elevated across prostate cancer progression resistance. Notably, both CRISPR-mediated knockout and targeted inhibition of Notch reversed enzalutamide resistance in vitro. Collectively, this study delineates dynamic alterations in Notch signaling activity during prostate cancer progression and establishes its function as a crucial and druggable driver of therapy resistance. These findings underscore Notch signaling as a promising therapeutic target to counteract resistance to AR-targeted therapies in advanced prostate cancer.

cancer biology↗

bioRxiv2025

Pan-cancer Analysis Identified Ectopic RUNX1T1 Associated with Lineage Plasticity

Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression, allowing cancer cells to rapidly alter their identity and evade targeted therapies. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the lack of pan-cancer gene markers quantifying lineage plasticity has limited its utility as a predictive biomarker. Homeobox (HOX) genes encode a family of transcription factors that play critical roles in embryonic development and tissue identity by establishing distinct expression patterns, known as HOX codes, in specific cell lineages. Through comprehensive bioinformatic analysis of multi-omics data--including expression profiles of 39 HOX genes from over 80,000 RNA sequencing samples across 114 cancer types--we first demonstrated that HOX codes effectively represent the lineages of cancer cells. We then identified multiple lineage-plastic cancer subtypes by applying the calculated HOX codes. Specifically, we identified lineage-plastic tumor subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), which exhibit altered HOX codes compared to non-plastic subtypes. Downstream differential expression analysis revealed significantly elevated RUNX1T1 levels across all three lineage-plastic cancer types, which was further validated through bulk and single-cell RNA sequencing data derived from preclinical and clinical samples. Together, our findings provide a novel strategy for characterizing lineage plasticity in pan-cancer cells and suggest ectopic RUNX1T1 expression as a pan-cancer marker and critical mediator of lineage plasticity.

cancer biology↗

bioRxiv2024

Hypothalamus-specific NSCs derived from hPSCs ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus

The hypothalamus is the brain region that regulates systemic body metabolism and multiple brain functions. The adult hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with age-related body changes, the hypothalamic NSC (htNSC) population declines, indicating the potential of htNSC replacement as an anti-aging strategy. Here, we developed protocol to generate htNSCs from human pluripotent stem cells (hPSCs). Implanting the hPSC-derived htNSCs into the hypothalamus of aged mice ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function. Mechanistically, these anti-aging effects were mediated by inter-tissue communication: enhanced neuronal activity in the htNSC-transplanted hypothalamus stimulated adipose tissues to produce and release the anti-aging molecule eNAMPT into systemic circulation via the sympathetic nervous system. Concurrently, the aged inflammatory environment in the hypothalamus was alleviated by peripheral anti-aging signals. Collectively, our findings support the potential of anti- or healthy aging therapies by targeting hypothalamus.

cell biology↗

bioRxiv2021

Testing in vitro toxicity of nanoparticles in 3D cell culture with various extracellular matrix scaffold

Nanomaterials are used in a variety of fields and toxicity assessment is paramount for their development and application. Although most toxicity assessments have been performed in 2D (2-Dimensional) cell culture, the inability to adequately replicate the in vivo environment and toxicity is a limitation. To overcome the limitation, a 3D (3-Dimensional) cell culture method has been developed to make an environment closer to an in vivo system. In this study, 20 nm SiO2 nanoparticles were dispersed in serum-containing (SC) and serum-free (SF) media to compare 2D cell culture and 3D cell culture toxicity. The cells were subjected to a 3D cell culture method in which HepG2, a human-derived liver cancer cell line, was mixed on a scaffold. We found that nanoparticles induced toxicity in 2D cell culture, but toxicity was not observed in 3D cell culture similar to in vivo environment. However, differences in toxicity were observed between the three types of scaffolds in the absence of serum as the number of cells decreased.

pharmacology and toxicology↗

bioRxiv2019

TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer

In treating patients with castration resistant prostate cancer (CRPC), enzalutamide, the second-generation androgen receptor (AR) antagonist, is an accepted standard of care. However, clinical benefits are limited to a median time of 4.8 months because resistance inevitably emerges. To determine the mechanism of treatment resistance, we carried out a RNA sequence analysis and found increased expression levels of neuroendocrine markers in the enzalutamide-resistant LNCaP human prostate cancer (CaP) cell line when compared to the parental cell line. Subsequent studies demonstrated that TCF4, a transcription factor implicated in Wnt signaling, mediated neuroendocrine differentiation (NED) in response to enzalutamide treatment and was elevated in the enzalutamide-resistant LNCaP. In addition, we observed that PTHrP mediated enzalutamide resistance in tissue culture and inducible TCF4 overexpression resulted in enzalutamide-resistance in a mouse xenograft model. Finally, small molecule inhibitors of TCF4 or PTHrP partially reversed enzalutamide resistance in CaP cells. When tissues obtained from men who died of metastatic CaP were examined, a positive correlation was found between the expression levels of TCF4 and PTHrP. Taken together, the current results indicate that TCF4 induces enzalutamide resistance via NED in CaP.

cancer biology↗