The drug-induced phenotypic landscape of colorectal cancer organoids.

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules.

PPARγ induces PD-L1 expression in MSS+ colorectal cancer cells.

Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor "programmed-cell-death-1" (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment. Peroxisome proliferator-activated-receptor-gamma (PPARγ), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPARγ induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage.

Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A.

Background: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA.

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant mice.

To identify novel hubs for cancer immunotherapy, we generated J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment.

The endocannabinoid N-arachidonoyl dopamine (NADA) selectively induces oxidative stress-mediated cell death in hepatic stellate cells but not in hepatocytes.

The endocannabinoid system is a crucial regulator of hepatic fibrogenesis. We have previously shown that the endocannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces death in hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, but not in hepatocytes. However, the effects of other endocannabinoids such as N-arachidonoyl dopamine (NADA) have not yet been investigated.

IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β-independent Smad signaling.

Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered a critical mediator of TGF-β-dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF in damaged liver. However, previous studies revealed that IL-13, rather than TGF-β, represents the predominant inducer of CTGF expression in HSCs.

Responsiveness of intestinal epithelial cell lines to lipopolysaccharide is correlated with Toll-like receptor 4 but not Toll-like receptor 2 or CD14 expression.

Background And Aims: Luminal bacteria have been implicated in the pathogenesis of inflammatory bowel diseases. Exposure of intestinal epithelial cells (IEC) to bacterial components potentially initiates intestinal inflammation by release of chemokines and recruitment of inflammatory cells. We analyzed receptor expression and signaling pathways involved in activation of human primary IEC and carcinoma-derived cell lines by lipopolysaccharide (LPS).

Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region.

Expression of IL-18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell-mediated chronic intestinal inflammation and anti-tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA).