Increased reflux secondary bile acids are associated with changes to the microbiome and transcriptome in Barrett's esophagus.

Bile acids are a major component of gastro-esophageal refluxate, thought to contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). As the microbiome shifts with EAC progression and bile acids influence bacterial composition, we examined these connections in a multi-center, cross-sectional study. We analyzed biospecimens from patients undergoing endoscopy using LC-MS to quantify bile acids in gastric aspirates, 16S rRNA sequencing for tissue microbiome profiling, and RNA sequencing on BE or cardia tissue.

A Cell Marker Atlas to Distinguish Metaplastic Transitions in Human Esophagus and Stomach.

Metaplasia is an adaptative response to injury and inflammation and can be a precursor to dysplasia and cancer. Metaplasia in the esophagus, termed Barrett's esophagus, is the replacement of the stratified squamous epithelium by glandular tissue comprising gastric and/or intestinal cell lineages. Metaplasia in the stomach can be divided further into pyloric metaplasia, in which corpus glands become more antral-like, or gastric intestinal metaplasia (GIM), in which gastric cells are replaced by intestinal cell lineages, with the latter subdivided into complete and incomplete.

Knowledge Discovery in Databases of Proteomics by Systems Modeling in Translational Research on Pancreatic Cancer.

Background: Knowledge discovery in databases (KDD) can contribute to translational research, also known as translational medicine, by bridging the gap between and studies, and clinical applications. Here, we propose a 'systems modeling' workflow for KDD.

Methods: This framework includes the data collection of a composition model (various research models), processing model (proteomics) and analytical model (bioinformatics, artificial intelligence/machine leaning and pattern evaluation), knowledge presentation, and feedback loops for hypothesis generation and validation.

Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis.

Unlabelled: Inflammation in the pancreas drives acinar-to-ductal metaplasia (ADM), a progenitor-like state that can be hijacked by mutant in the formation of pancreatic cancer (PDAC). How these cell fate decisions vary according to KRAS mutation remains poorly understood. To define mutation-specific lineage reversion and tumor initiation, we implement novel Ptf1a-TdTomato mice and multiple KRAS mutants across an array of genetic, pharmacologic, and inflammatory perturbations .

TransST: Transfer Learning Embedded Spatial Factor Modeling of Spatial Transcriptomics Data.

Background: Spatial transcriptomics have emerged as a powerful tool in biomedical research because of its ability to capture both the spatial contexts and abundance of the complete RNA transcript profile in organs of interest. However, limitations of the technology such as the relatively low resolution and comparatively insufficient sequencing depth make it difficult to reliably extract real biological signals from these data. To alleviate this challenge, we propose a novel transfer learning framework, referred to as TransST, to adaptively leverage the cell-labeled information from external sources in inferring cell-level heterogeneity of a target spatial transcriptomics data.

Mitochondrial Ca controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Endoplasmic reticulum to mitochondria Ca transfer is important for cancer cell survival, but the role of mitochondrial Ca uptake through the mitochondrial Ca uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (Mcu) ablated mitochondrial Ca uptake, which reduced proliferation and inhibited self-renewal.

Knowledge Discovery in Datasets of Proteomics by Systems Modeling in Translational Research on Pancreatic Cancer.

Knowledge discovery in databases (KDD) can contribute to translational research, also known as translational medicine, by bridging the gap between and studies and clinical applications. Here, we propose a 'systems modeling' workflow for KDD. This framework includes data collection of composition model (various research models) and processing model (proteomics) and analytical model (bioinformatics, artificial intelligence/machine leaning and pattern evaluation), knowledge presentation, and feedback loops for hypothesis generation and validation.

Proteomics profiling of research models for studying pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a five-year survival rate of 10-15% due to late-stage diagnosis and limited efficacy of existing treatments. This study utilized proteomics-based systems modelling to generate multimodal datasets from various research models, including PDAC cells, spheroids, organoids, and tissues derived from murine and human samples. Identical mass spectrometry-based proteomics was applied across the different models.

Squamous cell cancers of the aero-upper digestive tract: A unified perspective on biology, genetics, and therapy.

Squamous cell cancers (SCCs) of the head and neck, esophagus, and lung, referred to as aero-upper digestive SCCs, are prevalent in the United States and worldwide. Their incidence and mortality are projected to increase at alarming rates, posing diagnostic, prognostic, and therapeutic challenges. These SCCs share certain epigenetic, genomic, and genetic alterations, immunologic properties, environmental exposures, as well as lifestyle and nutritional risk factors, which may underscore common complex gene-environmental interactions across them.

LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.

Colorectal cancer (CRC) remains a leading cause of cancer death because of metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice.

Regulation of metastatic organotropism.

Metastasis is responsible for most cancer-related deaths. Different cancers have their own preferential sites of metastases, a phenomenon termed metastatic organotropism. The mechanisms underlying organotropism are multifactorial and include the generation of a pre-metastatic niche (PMN), metastatic homing, colonization, dormancy, and metastatic outgrowth.

FRA1 controls acinar cell plasticity during murine Kras-induced pancreatic acinar to ductal metaplasia.

Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during Kras acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing Kras.

Mitochondrial Ca controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Endoplasmic reticulum to mitochondria Ca transfer is important for cancer cell survival, but the role of mitochondrial Ca uptake through the mitochondrial Ca uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, deletion ( ) ablated mitochondrial Ca uptake, which reduced proliferation and inhibited self-renewal.

p53 at the crossroads of tumor immunity.

The p53 tumor suppressor protein has a plethora of cell-intrinsic functions and consequences that impact diverse cell types and tissues. Recent studies are beginning to unravel how wild-type and mutant p53 work in distinct ways to modulate tumor immunity. This sets up a disequilibrium between tumor immunosurveillance and escape therefrom.

Molecular Analysis of Persistent and Recurrent Barrett's Esophagus in the Setting of Endoscopic Therapy.

Introduction: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease.

An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription.

We have found that the ketogenic (Keto) diet is able to, unexpectedly, promote the metastatic potential of cancer cells in complementary mouse models. Notably, the Keto diet-induced tumor metastasis is dependent on BTB domain and CNC homolog 1 (BACH1) and its up-regulation of pro-metastatic targets, including cell migration-inducing hyaluronidase 1, in response to the Keto diet. By contrast, upon genetic knockout or pharmacological inhibition of endogenous BACH1, the Keto diet-mediated activation of those targets is largely diminished, and the effects on tumor metastasis are completely abolished.

Tumor niche network-defined subtypes predict immunotherapy response of esophageal squamous cell cancer.

Despite the promising outcomes of immune checkpoint inhibitors (ICIs), resistance to ICI presents a new challenge. Therefore, selecting patients for specific ICI applications is crucial for maximizing therapeutic efficacy. Herein, we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC.

Cancer-Associated Fibroblasts in Esophageal Cancer.

Cancer-associated fibroblasts (CAFs), a heterogenous population, can promote cancer cell proliferation, migration, invasion, immunosuppression, and therapeutic resistance in solid tumors. These effects are mediated through secretion of cytokines and growth factors, remodeling of the extracellular matrix, and providing metabolic support for cancer cells. The presence of CAFs in esophageal carcinoma are associated with reduced overall survival and increased resistance to chemotherapy and radiotherapy; thus, identifying therapeutic vulnerabilities of CAFs is a necessity.