Project description:The primary objective of this prospective observational study is to characterize the gut and oral microbiome as well as the whole blood transcriptome in gastrointestinal cancer patients and correlate these findings with cancer type, treatment efficacy and toxicity. Participants will be recruited from existing clinical sites only, no additional clinical sites are needed.
Project description:Deregulated gene expression is a hallmark of cancer, however most studies to date have analyzed short-read RNA-sequencing data with inherent limitations. Here, we combine PacBio long-read isoform sequencing (Iso-Seq) and Illumina paired-end short read RNA sequencing to comprehensively survey the transcriptome of gastric cancer (GC), a leading cause of global cancer mortality. We performed full-length transcriptome analysis across 10 GC cell lines covering four major GC molecular subtypes (chromosomal unstable, Epstein-Barr positive, genome stable and microsatellite unstable). We identify 60,239 non-redundant full-length transcripts, of which >66% are novel compared to current transcriptome databases. Novel isoforms are more likely to be cell-line and subtype specific, expressed at lower levels with larger number of exons, with longer isoform/coding sequence lengths. Most novel isoforms utilize an alternate first exon, and compared to other alternative splicing categories are expressed at higher levels and exhibit higher variability. Collectively, we observe alternate promoter usage in 25% of detected genes, with the majority (84.2%) of known/novel promoter pairs exhibiting potential changes in their coding sequences. Mapping these alternate promoters to TCGA GC samples, we identify several cancer-associated isoforms, including novel variants of oncogenes. Tumor-specific transcript isoforms tend to alter protein coding sequences to a larger extent than other isoforms. Analysis of outcome data suggests that novel isoforms may impart additional prognostic information. Our results provide a rich resource of full-length transcriptome data for deeper studies of GC and other gastrointestinal malignancies.
Project description:Colon cancer onset and progression is strongly associated with the presence, absence, or relative abundances of certain microbial taxa in the gastrointestinal tract. However, specific mechanisms affecting disease susceptibility related to complex commensal bacterial mixtures are poorly understood. We used a multi-omics approach to determine how differences in the complex gut microbiome (GM) influence the metabolome and host transcriptome and ultimately affect susceptibility to adenoma development. Fecal samples collected from a preclinical rat model of colon cancer harboring distinct complex GMs were analyzed using ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS). We collected samples prior to observable disease onset and identified putative metabolite profiles that predicted future disease severity, independent of GM status. Transcriptome analyses performed after disease onset from normal epithelium and tumor tissues between the high and low tumor GMs suggests that the GM is also correlated with altered host gene expression. Integrated pathway (IP) analyses of the metabolome and transcriptome based on putatively identified metabolic features indicate that bile acid biosynthesis was enriched in rats with high tumors (GM:F344) along with increased fatty acid metabolism and mucin biosynthesis. These data emphasize the utility of using untargeted metabolomics to reveal signatures of susceptibility and resistance and integrated analysis reveals common pathways that are likely to be universal targets for intervention.
Project description:Hypnea musciformis is a red macroalga that is widely distributed in tropical and subtropical regions. It is known to contain various bioactive compounds, including sulfated polysaccharides, flavonoids, and phlorotannins. Recent studies have investigated the potential anticancer effects of extracts from Hypnea musciformis demonstrating their have cytotoxic effects on various cancer cell lines. The anticancer effects of these extracts are thought to be due to the presence of bioactive compounds, which have been shown to have antitumor and immunomodulatory effects. However, further studies are needed to fully understand the molecular mechanisms that underlie these anticancer effects and to determine their potential as therapeutic agents for cancer treatment. We have performed transcriptome and proteome analysis in liver and colon cancer human cell lines following treatment with Hypnea musciformis macroalgae extracts to characterize its anti-tumor effect in detail at the molecular level and to link transcriptome and proteome responses to the observed phenotypes in vitro. We have identified that treatment with the macroalgae extract triggers p53-mediated response at the transcriptional and protein level in liver cancer cells, in contrast to colon cancer cells in which the effects are associated with metabolic changes. Overall, the available evidence suggests that extracts from Hypnea musciformis have the potential to serve as a source of anticancer agents in liver cancer cells through the activation of a p53-mediated anti-tumor response that is linked to inhibition of cellular proliferation and induction of apoptosis.