Biology subjects

Wang, S. C.

Publications and source records attributed to Wang, S. C..

7 recordsLinked to original sources

bioRxiv2026

Tumor context determines ARID1A effects on gastric cancer immunity

The role of ARID1A in cancer immune evasion remains uncertain, with prior studies reaching opposing conclusions. In addition, previous work has shown that the role of ARID1A in cell-autonomous tumorigenesis is context-dependent. Using isogenic murine gastric cancer models, we found that in vivo Arid1a loss in an autochthonous genetically engineered mouse model of gastric cancer conferred T cell-dependent immune evasion, while in vitro deletion did not. Mechanistically, tumor Arid1a loss reprogrammed the tumor microenvironment into an immune desert through suppression of GM-CSF secretion and interferon-{gamma} responsiveness. These changes were not observed when Arid1a was deleted in vitro. In human gastric cancer, an immune-cold phenotype was restricted to ARID1A mutants in the genomically stable subtype, while ARID1A loss in the chromosomal instability subtype was associated with variable immune profiles. These results demonstrate that tumor ARID1A loss does not intrinsically confer pro- or anti-tumor immune properties and instead is determined by tissue context.

cancer biology↗

bioRxiv2024

Deep Gaussian Process with Uncertainty Estimation for Microsatellite Instability and Immunotherapy Response Prediction Based on Histology

Determining tumor microsatellite status has significant clinical value because tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) respond well to immune check-point inhibitors (ICIs) and oftentimes not to chemotherapeutics. We propose MSI-SEER, a deep Gaussian process-based Bayesian model that analyzes H&E whole-slide images in weakly-supervised-learning to predict microsatellite status in gastric and colorectal cancers. We performed extensive validation using multiple large datasets comprised of patients from diverse racial backgrounds. MSI-SEER achieved state-of-the-art performance with MSI prediction, which was by integrating uncertainty prediction. We achieved high accuracy for predicting ICI responsiveness by combining tumor MSI status with stroma-to-tumor ratio. Finally, MSI-SEERs tile-level predictions revealed novel insights into the role of spatial distribution of MSI-H regions in the tumor microenvironment and ICI response.

bioinformatics↗

bioRxiv2024

In a nutshell: pistachio genome and kernel development

Pistachio is a sustainable nut crop with exceptional climate resilience and nutritional value. To advance pistachios as a future food source and a model system for hard-shelled fruits, we generated a chromosome-scale reference genome of the most widely grown pistachio cultivar (Pistacia vera Kerman) and a spatiotemporal developmental study of the hull, shell, and kernel. Our study defined four distinct stages of pistachio growth and maturation by integrating tissue-level physiological and molecular data from thousands of nuts across twenty-four time points over three growing seasons. Transcriptional and metabolic changes in the kernel elucidate molecular pathways governing nutritional quality, such as the accumulation of unsaturated fatty acids, which are vital for shelf-life and dietary value. This work yields new knowledge and resources that will inform other woody crops and facilitate further improvement of pistachio as a globally significant, sustainable, and nutritious crop.

plant biology↗

bioRxiv2024

Development of subunit selective proteasome substrates for Schistosoma species

Schistosomiasis, or bilharzia, is a neglected tropical disease caused by Schistosoma spp. blood flukes that infects over 200 million people worldwide. Just one partially effective drug is available, and new drugs and drug targets would be welcome. The 20S proteasome is a validated drug target for many parasitic infections, including those caused by Plasmodium and Leishmania. We previously showed that anticancer proteasome inhibitors that act through the Schistosoma mansoni 20S proteasome (Sm20S) kill the parasite in vitro. To advance these initial findings, we employed Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) to define the substrate cleavage specificities of the three catalytic {beta} subunits of purified Sm20S. The profiles in turn were used to design and synthesize subunit-specific optimized substrates that performed two to eight fold better than the equivalent substrates used to measure the activity of the constitutive human proteasome (c20S). These specific substrates also eliminated the need to purify Sm20S from parasite extracts - a single step enrichment was sufficient to accurately measure substrate hydrolysis and its inhibition with proteasome inhibitors. Finally, we show that the substrate and inhibition profiles for the 20S proteasome from the three medically important schistosome species are similar, suggesting that data arising from an inhibitor development campaign that focuses on Sm20S can be extrapolated to the other two targets with consequent time and cost savings.

biochemistry↗

bioRxiv2020

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

The dynamic regulation of {beta}-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of {beta}-cell regeneration. Arid1a is highly expressed in quiescent {beta}-cells but is physiologically suppressed when {beta}-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that {beta}-cell specific Arid1a deletion could potentiate {beta}-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling. Functionally, ERBB3 overexpression in {beta}-cells was sufficient to protect against diabetes, and chemical inhibition of ERBB or NR4A was able to block increased regeneration associated with Arid1a loss. mSWI/SNF complex activity is a barrier to {beta}-cell regeneration in physiologic and disease states.

genetics↗

bioRxiv2019

Hispanic/Latino gastric adenocarcinoma patients have distinct molecular profiles including a high rate of germline CDH1 mutations

Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes as compared to patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients were included in previous studies. We performed a large, integrated genomic analysis of gastric cancer samples from Hispanic/Latino patients. Whole-exome sequencing (WES) and RNA sequencing were performed on 57 Hispanic/Latino gastric cancer patient samples. Germline analysis was conducted on 83 patients. Functional testing of CDH1 germline mutations was performed in Chinese hamster ovary cells. Tumors from Hispanic/Latino patients were significantly enriched for the genomically-stable subtype (as defined by The Cancer Genome Atlas), compared to Asians and Whites (65% vs 21% vs 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type gastric cancer, 7 (16%) had germline mutations in CDH1. Mutation carriers were significantly younger than non-carriers (41 vs 50 years, P < 0.05). E-cadherin expression was reduced in 5 of 6 mutation carrier tumor samples available for analysis. In silico algorithms predicted 5 variants were deleterious. For the two variants that were predicted to be benign, we demonstrated that the mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino gastric cancer patients possess unique genomic landscapes. This includes a high rate of CDH1 germline mutations that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary.

cancer biology↗

bioRxiv2018

Untargeted Mass Spectrometry-Based Metabolomics Tracks Molecular Changes in Raw and Processed Foods and Beverages

A major aspect of our daily lives is the need to acquire, store and prepare our food. Storage and preparation can have drastic effects on the compositional chemistry of our foods, but we have a limited understanding of the temporal nature of processes such as storage, spoilage, fermentation and brewing on the chemistry of the foods we eat. Here, we performed a temporal analysis of the chemical changes in foods during common household preparations using untargeted mass spectrometry and novel data analysis approaches. Common treatments of foods such as home fermentation of yogurt, brewing of tea, spoilage of meats and ripening of tomatoes altered the chemical makeup through time, through both chemical and biological processes. For example, brewing tea altered its composition by increasing the diversity of molecules, but this change was halted after 4 min of brewing. The results indicate that this is largely due to differential extraction of the material from the tea and not modification of the molecules during the brewing process. This is in contrast to the preparation of yogurt from milk, spoilage of meat and the ripening of tomatoes where biological transformations directly altered the foods molecular composition. Comprehensive assessment of chemical changes using multivariate statistics showed the varied impacts of the different food treatments, while analysis of individual chemical changes show specific alterations of chemical families in the different food types. The methods developed here represent novel approaches to studying the changes in food chemistry that can reveal global alterations in chemical profiles and specific transformations at the chemical level.\n\nO_LSTHighlightsC_LSTO_LIWe created a reference data set for tomato, milk to yogurt, tea, coffee, turkey and beef.\nC_LIO_LIWe show that normal preparation and handling affects the molecular make-up.\nC_LIO_LITea preparation is largely driven by differential extraction.\nC_LIO_LIFormation of yogurt involves chemical transformations.\nC_LIO_LIThe majority of meat molecules are not altered in 5 days at room temperature.\nC_LI

biochemistry↗