Biology subjects

Park, Y. M.

Publications and source records attributed to Park, Y. M..

10 recordsLinked to original sources

bioRxiv2026

MCT4-Associated Lactate Export Defines Myeloid Metabolic Reprogramming during Head and Neck Cancer Progression

Head and neck squamous cell carcinoma (HNSCC) develops within a metabolically remodeled tumor microenvironment, yet how metabolic programs evolve across specific cell populations during tumor progression remains poorly understood. We integrated single-cell RNA-sequencing data from five HNSCC cohorts comprising 645,351 cells from 114 patients and inferred metabolic flux using single-cell Flux Estimation Analysis (scFEA). Myeloid cells showed the highest and most consistent metabolic allocation to lactate export among major cell types. In ten patients with paired normal mucosa and carcinoma, myeloid lactate-export allocation increased from 1.72% to 3.31% of total inferred metabolic flux, with an increase in every patient. SPP1+ macrophages showed the highest lactate-export allocation in carcinoma. Lactate export was predominantly associated with MCT4/SLC16A3. In carcinoma, myeloid SLC16A3 expression exceeded SLC16A1 by 17-fold, and CPTAC-HNSCC confirmed tumor enrichment of MCT4 protein. Together, these findings identify increased MCT4-associated lactate export as a prominent feature of myeloid metabolic reprogramming during HNSCC progression.

cancer biology↗

bioRxiv2025

ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion

Transcriptional Intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers, yet how transcriptional ITH programs drive tumor metastasis and immune evasion in upper aerodigestive squamous cell carcinoma (UASCC) remains unclear. Through single-cell RNA sequencing analysis of UASCC cells and patient tumors, we uncovered a hybrid epithelial mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating both STAT1 and PD-L1 (CD274) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, ETS1-high tumors strongly correlated with poor survival and resistance to immune checkpoint blockade across multiple cohorts. Leveraging drug screens, we discovered that ETS1-high cancers are vulnerable to HSP90 inhibitors (e.g., Alvespimycin), which suppress ETS1 by disrupting HIF1A-mediated transcriptional activation. Together, our work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.

cancer biology↗

bioRxiv2025

Genetically Defined Organoid Models Reveal Mechanisms Driving Squamous Cell Neoplastic Evolution and Identify Potential Therapeutic Vulnerabilities

Upper aerodigestive squamous cell carcinoma (UASCC) is an aggressive and lethal neoplasm, with its early neoplastic transformation mechanisms remaining poorly understood. Here, we characterize over 25 genetically-defined organoid models derived from murine and human oral/esophageal tissues harboring key driver mutations. Double knockout of TP53 and CDKN2A induced morphological dysplasia, hyperproliferation, loss of squamous differentiation, and tumorigenicity, which were further exacerbated by additional driver mutations (e.g., PIK3CA, NOTCH1, KMT2C). Single-cell analysis revealed an expansion of quiescent basal cells and proliferative squamous cells, alongside a loss of differentiated squamous cells during malignant transformation. A distinct senescence program, regulated by ANXA1, was markedly diminished during early neoplastic evolution. Mechanistically, the ANXA1-SMAD3-p27KIP1 pathway was identified as a critical regulator of this senescence program, acting to suppress neoplastic features in organoid models. Lastly, our high-throughput, single-organoid-resolution drug screens unexpectedly revealed PIK3CA-driven organoids exhibited sensitivity to Mitomycin C and Onalespib. This study provides novel mechanistic insights into early neoplastic evolution and underscores the value of genetically-defined organoid models for investigating cancer biology and identifying targeted therapies.

cancer biology↗

bioRxiv2024

Genomic and single-cell characterization of patient-derived tumor organoid models of head and neck squamous cell carcinoma

Head and Neck Squamous Cell Carcinoma (HNSCC) remains a significant health burden due to tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. This study enrolled 31 HNSCC patients for the establishment of patient-derived tumor organoids (PDOs), which faithfully maintained genomic features and histopathological traits of primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, correlating ex vivo drug sensitivity with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition (hEMT)-like ITH program is associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin (AREG) as a potential regulator of the hybrid epithelial/mesenchymal state. Moreover, AREG contributes to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine. One Sentence SummaryThis study establishes patient-derived tumor organoids (PDOs) from 31 Head and Neck Squamous Cell Carcinoma (HNSCC) patients, faithfully recapitulating characteristics of primary tumors and accurately predicting clinical responses to cisplatin treatment. We reveal intertumoral heterogeneity within PDOs and a hybrid epithelial-mesenchymal transition (hEMT) program conferring cisplatin resistance, highlighting amphiregulin (AREG) as a regulator of cellular plasticity and potential therapeutic target for HNSCC treatment.

cancer biology↗

bioRxiv2023

Molecular identification of ALDH1A1 and SIRT2 in the astrocytic putrescine-to-GABA metabolic pathway

GABA ({gamma}-aminobutyric acid) is the primary inhibitory neurotransmitter in the CNS. In astrocytes, GABA is synthesized by degradation of putrescine by monoamine oxidase B (MAO-B), a process which is known to mediate tonic inhibition of neuronal excitability. This astrocytic tonic GABA and related enzymes are also reported to be involved in memory impairment in Alzheimers Disease, and therefore are potential therapeutic targets to rescue memory in AD patients. However, the enzymes downstream of MAO-B in this pathway have not been elucidated yet. To fill this gap in knowledge, we performed transcriptomic and literature database analysis and identified Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and a histone deacetylase enzyme Sirtuin2 (SIRT2) as plausible candidate enzymes in primary cultured astrocytes. Immunostaining, metabolite analyses, and sniffer patch clamp performed in the presence or absence of suitable inhibitors, or with genetic ablation of the candidate enzymes recapitulated their participation in GABA production. We propose ALDH1A1 and SIRT2 as potential therapeutic targets against Alzheimers Disease.

neuroscience↗

bioRxiv2021

HEAT SHOCK FACTOR BINDING PROTEIN limits meiotic crossovers by repressing HEI10 transcription

The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a sensitive fluorescent seed crossover reporter in Arabidopsis thaliana we identify heat shock factor binding protein (HSBP) as a repressor of HEI10 transcription and crossover numbers. Using genome-wide crossover mapping and cytogenetics, we show that hsbp mutations or meiotic HSBP knockdowns increase ZMM-dependent crossovers towards the telomeres, mirroring the effects of HEI10 overexpression. Through RNA sequencing, DNA methylome and chromatin immunoprecipitation analysis, we reveal that HSBP directly represses HEI10 transcription by binding with heat shock factors (HSFs) at the HEI10 promoter and maintaining DNA methylation over the HEI10 5' untranslated region. Our findings provide insights into how the temperature response regulator HSBP restricts meiotic HEI10 transcription and crossover number by attenuating HSF activity.

plant biology↗

bioRxiv2021

Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimers Disease

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (A{beta}) plaques and significant progressive memory loss. In AD, astrocytes are known to take up and clear A{beta} plaques. However, how A{beta} induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas A{beta}-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene-silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic by-products ammonia, H2O2, and GABA to recover from reactive astrogliosis and memory impairment in AD model. Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial A{beta} detoxification and detrimental memory impairment in AD. We propose ODC1-inhibition as a promising therapeutic strategy for AD to facilitate removal of toxic molecules and prevent memory loss.

neuroscience↗

bioRxiv2021

Visualization of reactive astrocytes in living brain of Alzheimer's disease patient

An early appearance of reactive astrocytes is a hallmark of Alzheimers disease (AD)1,2, providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

neuroscience↗

bioRxiv2021

Visualizing reactive astrogliosis extends survival in glioblastoma patients

Glioblastoma multiforme (GBM) is a devastating brain tumor with dismal prognosis of only 15-month survival regardless of surgical resection. Here, we report an advanced neuroimaging technique combining 11C-acetate PET and MRI (AcePET), visualizing the boundary beyond the MRI-defined tumor. Targeted biopsy of the regions with increased 11C-acetate uptake revealed the presence of reactive astrocytes with enhanced acetate-transporter MCT1, along with cancer stem cells. Reactive astrogliosis and MCT1-dependent 11C-acetate-uptake were recapitulated in U87MG-orthotopic models. Mechanistically, glycolytic tumor cells release excessive acetate causing reactive astrogliosis, leading to the release of aberrant astrocytic GABA and H2O2, which further down-regulate the neuronal glucose uptake through GLUT3. Clincally, AcePET-guided surgery allows complete tumor resection of infiltrating cancer stem cells and extends the overall survival of patients by 5.25 months compared to conventional MRI-guided surgery. We established a new concept of the metabolic interactions between GBM cells and neighboring neurons through reactive astrocytes and developed AcePET-guided surgery to fight against GBM.

cancer biology↗

bioRxiv2019

Single-cell transcriptome analysis revealed a role of the transcription factor TOX in promoting CD8+ T-cell exhaustion in cancer

BackgroundT cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T-cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy. MethodsWe analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8+ T-cell population based on PDCD1 (PD-1) levels, i.e. PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T-cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8+ T cells was confirmed by single-cell trajectory and flow-cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses. ResultsWe retrieved many known factors for regulating T-cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8+ T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8+ T cells become more exhausted. Flow-cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T-cell exhaustion. TOX knockdown in the human TI CD8+ T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T-cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC. ConclusionsWe predicted the regulatory factors involved in T-cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8+ T-cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T-cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.

cancer biology↗