Biology subjects

Suh, J. M.

Publications and source records attributed to Suh, J. M..

8 recordsLinked to original sources

bioRxiv2026

Systematic identification of chromatin organizers as tuners of intratumoral heterogeneity

Intratumoral transcriptional heterogeneity (ITH) enables tumor cells to explore diverse phenotypic states, fueling therapeutic resistance and metastatic progression. Yet systematic approaches for identifying non-genetic regulators of this phenotype have been lacking. Here, we develop a multi-scale screening framework that integrates bulk patient transcriptomics, functional in vivo genetic screening, and single-cell transcriptomic and epigenomic profiling to nominate chromatin organizers that modulate ITH in breast cancer. From an initial set of 41 candidates nominated in silico, we identify RNF8 and MIS18A as factors whose perturbation produces coordinated shifts in transcriptomic variability and chromatin accessibility dispersion at the single-cell level, without altering mean expression or genomic copy number. MIS18A acts through a centromere-independent, DNA-methylation-associated pathway. Modulating RNF8 or MIS18A expression tunes chemotherapeutic sensitivity and metastatic potential in vivo: knockdown sensitizes cells and reduces metastatic burden, whereas overexpression confers resistance and promotes progression. Higher expression of both genes predicts shorter patient survival. These findings identify RNF8 and MIS18A as chromatin-level stochastic tuners of transcriptional variability in cancer and provide a generalizable framework for discovering regulators of non-genetic tumor heterogeneity.

cancer biology↗

bioRxiv2026

Systemic hypoxia suppresses solid tumor growth

Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.

cancer biology↗

bioRxiv2025

NADPH oxidase inhibitor enhances brain resilience in Alzheimer's disease by reducing tauopathy and neuroinflammation

Alzheimers disease associates closely with activation of NADPH oxidase (Nox) isozymes. We identified that CRB-2131, a novel oxadiazole derivative, potently suppresses Nox isozymes. It inhibits reactive oxygen species production (ROS) by hippocampal neuronal and microglial cells and reduces microglial activation. Prophylactic (starting at 3.5 months of age) and therapeutic (starting at 6 months of age) oral administration with CRB-2131 for 10 weeks in 5XFAD mice reduced hippocampal superoxide levels, lipid peroxidation, Tau phosphorylation, and neuroinflammation. Prophylactic and therapeutic CRB-2131 treatment of 5XFAD mice restored their impaired cognition as shown by the novel-object recognition, Y-maze, and Morris water-maze tests. CRB-2131 treatment increased mature neurons, reduced apoptotic mature neurons, and elevated immature neurons in the hippocampus. Positron-emission tomography/computed-tomography imaging confirmed that CRB-2131 stimulated neuronal regeneration. CRB-2131 suppresses brain oxidation, tauopathy, and neuroinflammation, thereby preventing mature neuron death and promoting neuron regeneration. Ultimately, this fosters a resilient brain and protects cognition.

neuroscience↗

bioRxiv2024

Multiplexed mosaic tumor models reveal natural phenotypic variations in drug response within and between populations

Many agents that show promise in preclinical cancer models lack efficacy in patients due to patient heterogeneity that is not captured in traditional assays. To address this problem, we have developed GENEVA, a platform that measures the molecular and phenotypic consequences of drug perturbations within diverse populations of cancer cells at single-cell resolution, both in vitro and in vivo. Here, we apply GENEVA to study the KRAS G12C inhibitors, recapitulating known properties of these drugs and uncovering a previously unknown role for mitochondrial activation in cell death induced by KRAS inhibition. We demonstrate that this finding can be leveraged for the development of combination therapies with greater efficacy. Finally, we show that the application of GENEVA with in vivo mouse models revealed epithelial to mesenchymal transition (EMT) as a key mechanism for resistance to KRAS G12C inhibition.

cancer biology↗

bioRxiv2024

Systematic annotation of orphan RNAs reveals blood-accessible molecular barcodes of cancer identity and cancer-emergent oncogenic drivers

From extrachromosomal DNA to neo-peptides, the broad reprogramming of the cancer genome leads to the emergence of molecules that are specific to the cancer state. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression1. Here, we report a systematic and comprehensive search to identify, annotate, and characterize cancer-emergent oncRNAs across 32 tumor types. We also leverage large-scale in vivo genetic screens in xenografted mice to functionally identify driver oncRNAs in multiple tumor types. We have not only discovered a large repertoire of oncRNAs, but also found that their presence and absence represent a digital molecular barcode that faithfully captures the types and subtypes of cancer. Importantly, we discovered that this molecular barcode is partially accessible from the cell-free space as some oncRNAs are secreted by cancer cells. In a large retrospective study across 192 breast cancer patients, we showed that oncRNAs can be reliably detected in the blood and that changes in the cell-free oncRNA burden captures both short-term and long-term clinical outcomes upon completion of a neoadjuvant chemotherapy regimen. Together, our findings establish oncRNAs as an emergent class of cancer-specific non-coding RNAs with potential roles in tumor progression and clinical utility in liquid biopsies and disease monitoring.

cancer biology↗

bioRxiv2021

In vivo mitochondrial matrix proteome profiling reveals RTN4IP1/OPA10 as an antioxidant NADPH oxidoreductase

Targeting proximity labeling enzymes to specific cellular locations is a viable strategy for profiling subcellular proteomes. Here, we generated transgenic mice expressing a mitochondrial matrix-targeted ascorbate peroxidase (MAX-Tg) to analyze tissue-specific matrix proteomes. Desthiobiotin-phenol labeling of muscle tissues from MAX-Tg mice allowed for efficient profiling of mitochondrial-localized proteins in these tissues. Comparative analysis of matrix proteomes from MAX-Tg muscle tissues revealed differential enrichment of mitochondrial proteins related to energy production in between different muscle groups. Reticulon 4 interacting protein 1 (RTN4IP1), also known as Optic Atrophy-10 (OPA10), was highly enriched in the cardiac and soleus muscles and was found to localize to the mitochondrial matrix via a strong mitochondrial targeting sequence at its N-terminus. Protein structure analysis revealed that RTN4IP1 is an NADPH oxidoreductase with structural homology to bacterial quinone oxidoreductase. Enzymatic activity assays, interactome analysis, and metabolite profiling confirmed a function for RTN4IP1 in coenzyme Q (CoQ) biosynthesis. Rtn4ip1-knockout C2C12 cells had reduced CoQ9 levels, were vulnerable to oxidative stress, and had decreased oxygen consumption rates and ATP production. Collectively, RTN4IP1 is a mitochondrial antioxidant NADPH oxidoreductase supporting oxidative phosphorylation activity in muscle tissue.

cell biology↗

bioRxiv2020

Dynamic tracking and identification of tissue-specific secretory proteins in the circulation of live mice

Here we describe iSLET (in situ Secretory protein Labeling via ER-anchored TurboID) which labels secretory pathway proteins as they transit through the ER-lumen to enable dynamic tracking of tissue-specific secreted proteomes in vivo. We expressed iSLET in the mouse liver and demonstrated efficient in situ labeling of the liver-specific secreted proteome which could be tracked and identified within circulating blood plasma. iSLET is a versatile and powerful tool for studying spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets.

biochemistry↗

bioRxiv2019

Obesity Potentiates TH2 Immunopathology via Dysregulation of PPAR

How obesity affects immune function is not well understood. Clinically, obesity is strongly associated with severe TH2 immunopathology1-3, though the physiological, cellular, and molecular underpinnings of this association remain obscure. Here, we demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans4,5. Mechanistically, we show that dysregulation of the nuclear hormone receptor (NHR) PPAR{gamma} (peroxisome proliferator-activated receptor gamma) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPAR{gamma} oversees a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 priming and effector cytokine interleukin-4 (IL-4). Accordingly, thiazolidinediones (TZDs), potent PPAR{gamma} agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPAR{gamma} as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology. Fundamentally, these findings demonstrate that shifting physiologic metabolic states can shape the tone of adaptive immune responses to modulate differential disease susceptibility.

immunology↗