Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression.

Background: Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models.

Objective: We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum.

Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established.

NetMIM: network-based multi-omics integration with block missingness for biomarker selection and disease outcome prediction.

Compared with analyzing omics data from a single platform, an integrative analysis of multi-omics data provides a more comprehensive understanding of the regulatory relationships among biological features associated with complex diseases. However, most existing frameworks for integrative analysis overlook two crucial aspects of multi-omics data. Firstly, they neglect the known dependencies among biological features that exist in highly credible biological databases.

Robust analysis of allele-specific copy number alterations from scRNA-seq data with XClone.

Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data.

Inhibition of Aberrantly Overexpressed Polo-like Kinase 4 Is a Potential Effective Treatment for DNA Damage Repair-Deficient Uterine Leiomyosarcoma.

Purpose: Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment.

Deep Learning-Based 3D Single-Cell Imaging Analysis Pipeline Enables Quantification of Cell-Cell Interaction Dynamics in the Tumor Microenvironment.

Unlabelled: The three-dimensional (3D) tumor microenvironment (TME) comprises multiple interacting cell types that critically impact tumor pathology and therapeutic response. Efficient 3D imaging assays and analysis tools could facilitate profiling and quantifying distinctive cell-cell interaction dynamics in the TMEs of a wide spectrum of human cancers. Here, we developed a 3D live-cell imaging assay using confocal microscopy of patient-derived tumor organoids and a software tool, SiQ-3D (single-cell image quantifier for 3D), that optimizes deep learning (DL)-based 3D image segmentation, single-cell phenotype classification, and tracking to automatically acquire multidimensional dynamic data for different interacting cell types in the TME.

Tumor-specific cholinergic CD4 T lymphocytes guide immunosurveillance of hepatocellular carcinoma.

Cholinergic nerves are involved in tumor progression and dissemination. In contrast to other visceral tissues, cholinergic innervation in the hepatic parenchyma is poorly detected. It remains unclear whether there is any form of cholinergic regulation of liver cancer.

Organoid cultures for cancer modeling.

Organoids derived from adult stem cells (ASCs) and pluripotent stem cells (PSCs) are important preclinical models for studying cancer and developing therapies. Here, we review primary tissue-derived and PSC-derived cancer organoid models and detail how they have the potential to inform personalized medical approaches in different organ contexts and contribute to the understanding of early carcinogenic steps, cancer genomes, and biology. We also compare the differences between ASC- and PSC-based cancer organoid systems, discuss their limitations, and highlight recent improvements to organoid culture approaches that have helped to make them an even better representation of human tumors.

ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer.

Targetable drivers governing 5-fluorouracil and cisplatin (5FU + CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Here, we establish 5FU + CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines.

Sex Differences in Association Between Gut Microbiome and Essential Hypertension Based on Ambulatory Blood Pressure Monitoring.

Background: Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association between GM and hypertension.

Methods: We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years).

Altered human gut virome in patients undergoing antibiotics therapy for Helicobacter pylori.

Transient gut microbiota alterations have been reported after antibiotic therapy for Helicobacter pylori. However, alteration in the gut virome after H. pylori eradication remains uncertain.

Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies.

Background: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown.

Mutational landscape of normal epithelial cells in Lynch Syndrome patients.

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients.

Dynamic changes in antibiotic resistance genes and gut microbiota after Helicobacter pylori eradication therapies.

Background: Short-term antibiotics exposure is associated with alterations in microbiota and antibiotic resistance genes (ARGs) in the human gut. While antibiotics are critical in the successful eradication of Helicobacter pylori, the short-term and long-term impacts on the composition and quantity of antibiotics resistance genes after H. pylori eradication are unclear.

Oncogenic mutations drive intestinal cancer initiation through paracrine remodeling.

Three articles in Nature show that intestinal stem cells with cancer-promoting mutations could shape the surrounding normal tissue in their favor to promote clonal fixation and field expansion, raising the possibility of developing therapeutic strategies that maintain or enhance the health of normal cells to out-compete the mutant cells.

A Three-Way Combinatorial CRISPR Screen for Analyzing Interactions among Druggable Targets.

We present a CRISPR-based multi-gene knockout screening system and toolkits for extensible assembly of barcoded high-order combinatorial guide RNA libraries en masse. We apply this system for systematically identifying not only pairwise but also three-way synergistic therapeutic target combinations and successfully validate double- and triple-combination regimens for suppression of cancer cell growth and protection against Parkinson's disease-associated toxicity. This system overcomes the practical challenges of experimenting on a large number of high-order genetic and drug combinations and can be applied to uncover the rare synergistic interactions between druggable targets.

Evaluation of Experimental Protocols for Shotgun Whole-Genome Metagenomic Discovery of Antibiotic Resistance Genes.

Shotgun metagenomics has enabled the discovery of antibiotic resistance genes (ARGs). Although there have been numerous studies benchmarking the bioinformatics methods for shotgun metagenomic data analysis, there has not yet been a study that systematically evaluates the performance of different experimental protocols on metagenomic species profiling and ARG detection. In this study, we generated 35 whole genome shotgun metagenomic sequencing data sets for five samples (three human stool and two microbial standard) using seven experimental protocols (KAPA or Flex kits at 50ng, 10ng, or 5ng input amounts; XT kit at 1ng input amount).

Discovering Cancer-Related miRNAs from miRNA-Target Interactions by Support Vector Machines.

MicroRNAs (miRNAs) have been shown to be closely related to cancer progression. Traditional methods for discovering cancer-related miRNAs mostly require significant marginal differential expression, but some cancer-related miRNAs may be non-differentially or only weakly differentially expressed. Such miRNAs are called dark matters miRNAs (DM-miRNAs) and are targeted through the Pearson correlation change on miRNA-target interactions (MTIs), but the efficiency of their method heavily relies on restrictive assumptions.

Breakthrough Moments: Organoid Models of Cancer.

Five years ago, Li et al. (2014) and Gao et al. (2014) reported the power and unique advantages of cancer organoids.

Establishing Pure Cancer Organoid Cultures: Identification, Selection and Verification of Cancer Phenotypes and Genotypes.

Precision medicine requires in vitro models which will both faithfully recapitulate the features of an individual's disease and enable drug testing on a wide variety of samples covering the greatest range of phenotypes possible for a particular disease. Organoid technology has immense potential to fulfill this demand, but it will be necessary to develop robust protocols that enable the generation of organoids in a dependable manner from nearly every patient. Here we provide a user's guide, including detailed step-by-step protocols, to the establishment, isolation and verification of gastric cancer organoids.

DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer.

Background: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA).

Results: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.

A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening.

Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis.

PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation.

Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids.