A framework to mine laser microdissection-based omics data and uncover regulators of pancreatic cancer heterogeneity.

Background: Pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of pancreatic cancer, exhibits profound intratumor morphological heterogeneity, complicating the elucidation of the underlying molecular mechanisms driving its progression.

Results: We present and validate an optimized framework for RNA sequencing (RNA-seq) of multiple spatially resolved laser micro-dissected tumor areas (LMD-seq), along with methodological and analytical details to maximize reproducibility and data mining. This approach enhances sensitivity in detecting lowly expressed genes, outperforming single-cell RNA-seq methods, particularly in identifying rare tumor cell populations and transcriptional programs with low expression.

CellHit: a web server to predict and analyze cancer patients' drug responsiveness.

We present the CellHit web server (https://cellhit.bioinfolab.sns.

Learning and actioning general principles of cancer cell drug sensitivity.

High-throughput screening of drug sensitivity of cancer cell lines (CCLs) holds the potential to unlock anti-tumor therapies. In this study, we leverage such datasets to predict drug response using cell line transcriptomics, focusing on models' interpretability and deployment on patients' data. We use large language models (LLMs) to match drug to mechanisms of action (MOA)-related pathways.

WNT Oncogenic Transcription Requires MYC Suppression of Lysosomal Activity and EPCAM Stabilization in Gastric Tumors.

Background & Aims: WNT signaling is central to spatial tissue arrangement and regulating stem cell activity, and it represents the hallmark of gastrointestinal cancers. Although its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive.

Methods: We have developed mouse models to control the specific expression of an oncogenic form of β-catenin (CTNNB1) in combination with MYC activation in Lgr5 cells of the gastric antrum.

The landscape of cancer-rewired GPCR signaling axes.

We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns.

Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer.

Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming.

Acetyl-CoA production by Mediator-bound 2-ketoacid dehydrogenases boosts de novo histone acetylation and is regulated by nitric oxide.

Histone-modifying enzymes depend on the availability of cofactors, with acetyl-coenzyme A (CoA) being required for histone acetyltransferase (HAT) activity. The discovery that mitochondrial acyl-CoA-producing enzymes translocate to the nucleus suggests that high concentrations of locally synthesized metabolites may impact acylation of histones and other nuclear substrates, thereby controlling gene expression. Here, we show that 2-ketoacid dehydrogenases are stably associated with the Mediator complex, thus providing a local supply of acetyl-CoA and increasing the generation of hyper-acetylated histone tails.

Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription.

Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic -regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination does not involve nascent RNA cleavage, and its interplay with other termination machineries is unclear.

Cancer Evolution: A Multifaceted Affair.

Unlabelled: Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution.

The landscape of cancer rewired GPCR signaling axes.

We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes, which revealed that multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulated pathway activity signatures from metabolomics datasets, providing valuable surrogate information for GPCRs responding to organic ligands.

DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon.

Genetic variants in the DNA methyltransferase 3 A (DNMT3A) locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function.

Clonal hematopoiesis, inflammation, and cardiovascular disorders: a mitochondrial connection.

Mutations in two antagonistic regulators of DNA methylation, DNMT3A and TET2, are associated with clonal hematopoiesis and increased risk of cardiovascular disorders. Recently, Cobo et al. traced the mechanistic bases for such links to loss of mitochondrial integrity, cytoplasmic dispersion of mitochondrial DNA, and the subsequent activation of interferon-stimulated genes (ISGs) in macrophages.

Interferon regulatory factor 1 (IRF1) controls the metabolic programmes of low-grade pancreatic cancer cells.

Objective: Pancreatic ductal adenocarcinomas (PDACs) include heterogeneous mixtures of low-grade cells forming pseudoglandular structures and compact nests of high-grade cells organised in non-glandular patterns. We previously reported that low-grade PDAC cells display high expression of interferon regulatory factor 1 (IRF1), a pivotal transcription factor of the interferon (IFN) system, suggesting grade-specific, cell-intrinsic activation of IFN responses. Here, we set out to determine the molecular bases and the functional impact of the activation of IFN-regulated responses in human PDACs.

H3K9 trimethylation in active chromatin restricts the usage of functional CTCF sites in SINE B2 repeats.

Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification controlling constitutive heterochromatin, gene repression, and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin domains to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the impact of SETDB1 on stimulus-inducible gene expression in macrophages, we found that loss of H3K9me3 caused by SETDB1 depletion was associated with increased recruitment of CTCF to >1600 DNA binding motifs contained within SINE B2 repeats, a previously unidentified target of SETDB1-mediated repression.

RFX transcription factors control a miR-150/PDAP1 axis that restrains the proliferation of human T cells.

Within the immune system, microRNAs (miRNAs) exert key regulatory functions. However, what are the mRNA targets regulated by miRNAs and how miRNAs are transcriptionally regulated themselves remain for the most part unknown. We found that in primary human memory T helper lymphocytes, miR-150 was the most abundantly expressed miRNA, and its expression decreased drastically upon activation, suggesting regulatory roles.

Lower probability and shorter duration of infections after COVID-19 vaccine correlate with anti-SARS-CoV-2 circulating IgGs.

The correlation between immune responses and protection from SARS-CoV-2 infections and its duration remains unclear. We performed a sanitary surveillance at the European Institute of Oncology (IEO) in Milan over a 17 months period. Pre-vaccination, in 1,493 participants, we scored 266 infections (17.

Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis.

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS.

Integration of transcriptional and metabolic control in macrophage activation.

Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and stimulus-specific changes in gene expression programs accompanied by extensive rewiring of metabolism, with alterations in chromatin modifications providing one layer of integration of transcriptional and metabolic regulation. A systematic and mechanistic understanding of the mutual influences between signal-induced metabolic changes and gene expression is still lacking.

ADP-ribosyltransferases, an update on function and nomenclature.

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases.

Induction of OCT2 contributes to regulate the gene expression program in human neutrophils activated via TLR8.

The transcription factors (TFs) that regulate inducible genes in activated neutrophils are not yet completely characterized. Herein, we show that the genomic distribution of the histone modification H3K27Ac, as well as PU.1 and C/EBPβ, two myeloid-lineage-determining TFs (LDTFs), significantly changes in human neutrophils treated with R848, a ligand of Toll-like receptor 8 (TLR8).