Biology subjects

Tran, H. N.

Publications and source records attributed to Tran, H. N..

5 recordsLinked to original sources

bioRxiv2026

Ex vivo human tumor slices more accurately predict patient responses to an oncolytic virus than in vivo mouse models

Immunotherapies, including oncolytic viruses (OV), are promising therapies that can enhance anti-tumor immune responses. However, preclinical success of immunotherapies in mouse models has not always translated to clinical benefit in cancer patients. This study compared preclinical efficacy and mechanism of action for ASP9801, a vaccinia virus expressing IL-7 and IL-12, using mouse models of colorectal cancer (CRC) in vivo and in human organotypic tumor slice models ex vivo. The murine surrogate for ASP9801 significantly reduced tumor volumes in treated and abscopal tumors in two different CRC models in vivo (MC38 and RO100). Treatment efficacy was accentuated when combined with anti-PD1 treatment, and single-cell RNA sequencing analysis revealed depletion of tumor cells and increased T cell infiltration and activation in both treated and abscopal tumors. However, human tissue analysis ex vivo (E-slices) using PDX models and patient samples showed that ASP9801 is not effective in CRC, consistent with clinical trial results. On the other hand, ASP9801 was highly effective in GBM, indicating indication-specific efficacy of ASP9801, and how E-slice assays can be used to identify treatment-sensitive indications. This study demonstrates the superiority of E-slices over mouse models for predicting clinical response and its utility in planning clinical trials.

cancer biology↗

bioRxiv2026

Integrative host transcriptomic and mucosal microbiome profiling reveals region-specific host-microbiome associations across the human intestine

Host genetics shapes gut microbiome composition, yet the physiological mechanisms underlying this relationship remain poorly understood. Characterizing associations between host gene expression and the mucosal microbiome offers a promising route to identifying the host pathways and microbial taxa most likely to interact physiologically. However, existing investigations have been conducted primarily in acute disease contexts and within the colon, leaving host-microbiome associations outside of acute inflammatory contexts and those in undersampled regions such as the terminal ileum poorly characterized. To address these gaps, we profiled paired host gene expression from full-thickness resections and mucosal microbiome data, both from macroscopically non-inflamed tissue from Crohns disease patients undergoing surgery across three intestinal sites: terminal ileum (n = 32), cecum (n = 35), and right colon (n = 30). Using a multi-level analytical framework including Procrustes analysis, sparse canonical correlation analysis, and elastic net regression, we identified significant associations between the mucosal transcriptome and microbiome. Intestine-wide, genes enriched in immune and intestinal barrier integrity pathways were associated with heritable taxa including Fusicatenibacter, consistent with patterns observed in microbiome genome-wide association studies. Region-specific analysis identified the terminal ileum as a distinct site of host-microbiome interaction, with associations involving metabolic and barrier-related pathways not observed in the large intestine. Notable terminal ileum-specific associations included PCDH20 with Faecalitalea and ACAT1 with Lactococcus, implicating epithelial barrier maintenance and host-microbiome metabolic interactions, respectively. These findings advance our understanding of the physiological basis of host-microbiome interactions across the intestine. ImportanceThe human gut is home to trillions of microorganisms that interact with the intestinal lining, yet we have a limited understanding of the specific biological processes involved in these interactions. Most studies characterizing the relationships between host gene expression and the gut microbiome have focused on the colon and on active disease contexts, leaving it unclear whether the associations observed reflect fundamental host-microbiome biology or disease-specific responses. By examining mucosal tissue, where host cells and microbes are in direct contact, across three sites in non-acutely inflamed tissue, we show that expression of immune defense and barrier maintenance genes is broadly associated with the microbiome across the intestine. We also identify distinct classes of associations in the terminal ileum, including host genes involved in metabolic processes. These findings provide a foundation for understanding how host biology and the gut microbiome are linked outside of acute disease.

genomics↗

bioRxiv2026

SCiMS: Sex Calling in Metagenomic Sequences

BackgroundHost sex is a critical determinant of microbial community structure across many host species, influenced by hormonal profiles, physiology, and sex-stratified behaviors. Despite its importance, sex metadata is frequently missing in microbiome studies, including for animal-associated samples. Host chromosomal sex can be inferred from the host-derived reads present in metagenomic data, but existing genomic sex prediction tools rely on fixed coverage thresholds calibrated for human XY chromosomes and require relatively high host reads, limiting their use on low host-biomass samples such as stool and on organisms with other sex-determination systems. ResultsHere, we present SCiMS (Sex Calling in Metagenomic Sequences), a bioinformatic tool that leverages host-derived DNA within shotgun metagenomic data to predict host chromosomal sex, even at low host coverage. SCiMS uses a multinomial likelihood computed from observed read counts under each sex and reports chromosomal sex calls. Because the expected read distribution is derived directly from chromosome lengths and ploidy under each candidate karyotype, SCiMS applies to any organism with a heterogametic sex-determination system. We benchmarked SCiMS against existing tools on simulated metagenomic data, human metagenomic samples spanning multiple body sites, and metagenomic samples from seven animal species. SCiMS matched or outperformed existing tools, with its noticeable advantage at low host read conditions. ConclusionsSCiMS provides an accurate, scalable, and cross-species generalizable solution for host chromosomal sex classification, even when host DNA is minimal. By enabling recovery of missing sex metadata, it serves as a quality-control tool analyses in microbiome research. SCiMS is freely available at http://github.com/davenport-lab/SCiMS.

bioinformatics↗

bioRxiv2024

Combined inhibition of S100A4 and TIGIT suppresses late-stage breast cancer metastasis to the lung by activating T and NK cells

Cancer metastasis is responsible for approximately 90% of cancer-related deaths, but very few treatment options exist currently. While the role of S100A4 in promoting metastasis has been known for decades, this knowledge has not been translated in the clinic. Here, we report that a novel monoclonal antibody against the human S100A4 protein (S1004-11) effectively suppresses breast cancer metastasis in two different mouse models. Importantly, a novel combination of ant-TIGIT and S100A4-11 can suppress lung metastases even in late-stage disease after the lung premetastatic niche (PMN) has already been established similar to a stage when many breast cancer patients are diagnosed. Mechanistically, S1004-11 mAb treatment block the formation of PMN by suppressing neutrophil infiltration and activating natural killer (NK) and T cells in the lung. Single-cell RNA-sequencing and cell:cell communication analyses indicate that TIGIT signaling suppresses NK cells, which is reversed in S100A4-11 treated PMN. In summary, this study provides compelling evidence for a novel mechanism of S100A4 function in PMN formation and the feasibility of using S100A4-11 monoclonal antibody to suppress metastases at different stages of breast cancer progression.

cancer biology↗

bioRxiv2022

Sex-biased Yap1 oncogene function

The incidence of many human cancers differs according to sex, but little is known about the interplay between oncogenic events and sex as a variable in tumorigenesis. Here we report that the oncogene Yap1 is sexually dimorphic in medulloblastoma progression and immune suppression. We show that Yap1 promotes stemness and blocks differentiation in sonic hedgehog (SHH)-subtype medulloblastoma by at least two distinct but complementary molecular mechanisms to regulate the RNA expression and protein functions of Sox2, Atoh1, NeuroD1, and Zic1/2. Yap1 also promotes an immune suppressive tumor microenvironment by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGF-{beta}, and CCL5 immune pathways. Notably, Yap1 function is more critical in males and this is evolutionarily conserved: genes downstream of YAP1 identified in mouse models stratify male but not female medulloblastoma patient survival. In summary, we demonstrate a sex-based function for an oncogene, underscoring the critical need to incorporate sex as a variable in cancer mechanism and clinical response studies, particularly those involving YAP1.

cancer biology↗