Biology subjects

Oh, W.

Publications and source records attributed to Oh, W..

3 recordsLinked to original sources

bioRxiv2025

High-fat circulating nutrients promote growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer

Diet influences the levels of small molecules that circulate in plasma and interstitial fluid, altering the biochemical composition of the tumor microenvironment (TME). These circulating nutrients have been associated with how tumors grow and respond to treatment, but it remains difficult to parse their direct effects on cancer cells. Here, we combine a three-dimensional (3D) microfluidic tumor model with physiologically relevant culture media to investigate how concentrations of circulating nutrients influence tumor growth, cancer cell invasion, and overall tumor metabolism. Human triple-negative breast cancer cells cultured in 2D under media conditions mimicking five different dietary states show no observable differences in proliferation or morphology. Nonetheless, those exposed to high-fat conditions exhibit increased metabolic activity and upregulate genes associated with motility and extracellular matrix remodeling. In the 3D microfluidic model, high-fat conditions accelerate tumor growth and invasion and induce the formation of hollow cavities. Surprisingly, the presence of these cavities does not correlate with an increase in apoptosis or ferroptosis. Instead, RNA-sequencing analysis revealed that high-fat conditions induce the expression of MMP1, consistent with cavitation via cell invasion. Mimicking the flow of circulating nutrients within the TME can thus be used to identify novel connections between metabolic states and tumor phenotype.

bioengineering↗

bioRxiv2023

Tumor cell-derived lactic acid inhibits the interaction of PD-L1 protein and PD-L1 antibody in the PD-L1/PD-1 blockade therapy-resistant tumor

Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nontheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings in this study provide a new mechanism of how lactic acid induces an immunosuppressive environment and suggest a potential combination treatment to overcome the PD-1/PD-L1 blockade therapy resistance.

cancer biology↗

bioRxiv2022

Multi-center integrated analysis of non-coding CRISPR screens

The ENCODE Consortiums efforts to annotate non-coding, cis-regulatory elements (CREs) have advanced our understanding of gene regulatory landscapes which play a major role in health and disease. Pooled, non-coding CRISPR screens are a promising approach for systematically investigating gene regulatory mechanisms. Here, the ENCODE Functional Characterization Centers report 109 screens comprising 346,970 individual perturbations across 13.3Mb of the genome, using a variety of methods, readouts, and statistical analyses. Across 332 functionally confirmed CRE-gene links, we identify principles for screening endogenous, non-coding elements for causal regulatory mechanisms. Nearly all CREs show strong evidence of open chromatin, and targeting accessibility peak summits is a critical component of our proposed sgRNA design rules. We provide experimental guidelines to accurately detect CREs with variable, often low, transcriptional effects. We discover a previously undescribed DNA strand-bias for CRISPRi in transcribed regions with implications for screen design and analysis. Benchmarking five screen analysis tools, we find CASA produces the most conservative CRE calls and is robust to artifacts of low-specificity sgRNAs. Together, we provide an accessible data resource, predesigned sgRNAs targeting 3,275,697 ENCODE SCREEN candidate CREs, and screening guidelines to accelerate functional characterization of the non-coding genome.

genomics↗