Glioma-induced alterations in excitatory neurons are reversed by mTOR inhibition.

Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging.

Mesenchymal GDNF promotes intestinal enterochromaffin cell differentiation.

Enteroendocrine cells (EECs) differentiate and mature to form functionally distinct populations upon migration along the intestinal crypt-villus axis, but how niche signals affect this process is poorly understood. Here, we identify expression of Glial cell line-derived neurotrophic factor (GDNF) in the intestinal subepithelial myofibroblasts (SEMFs), while the GDNF receptor RET was expressed in a subset of EECs, suggesting GDNF-mediated regulation. Indeed, GDNF-RET signaling induced increased expression of EEC genes including , encoding for the rate-limiting enzyme for 5-hydroxytryptamine (5-HT, serotonin) biosynthesis, and increased the frequency of 5-HT+ enterochromaffin cells (ECs) in mouse organoid culture experiments and .

Neuro-Mesenchymal Interaction Mediated by a β2-Adrenergic Nerve Growth Factor Feedforward Loop Promotes Colorectal Cancer Progression.

Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury.

The currently accepted intestinal epithelial cell organization model proposes that Lgr5 crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5 cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling.

Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition.

Gliomas are highly aggressive brain tumors characterized by poor prognosis and composed of diffusely infiltrating tumor cells that intermingle with non-neoplastic cells in the tumor microenvironment, including neurons. Neurons are increasingly appreciated as important reactive components of the glioma microenvironment, due to their role in causing hallmark glioma symptoms, such as cognitive deficits and seizures, as well as their potential ability to drive glioma progression. Separately, mTOR signaling has been shown to have pleiotropic effects in the brain tumor microenvironment, including regulation of neuronal hyperexcitability.

Role of PDGFRA cells and a CD55 PDGFRA fraction in the gastric mesenchymal niche.

PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identify regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA cells.

Development of a gene edited next-generation hematopoietic cell transplant to enable acute myeloid leukemia treatment by solving off-tumor toxicity.

Immunotherapy of acute myeloid leukemia (AML) has been challenging because the lack of tumor-specific antigens results in "on-target, off-tumor" toxicity. To unlock the full potential of AML therapies, we used CRISPR-Cas9 to genetically ablate the myeloid protein CD33 from healthy donor hematopoietic stem and progenitor cells (HSPCs), creating tremtelectogene empogeditemcel (trem-cel). Trem-cel is a HSPC transplant product designed to provide a reconstituted hematopoietic compartment that is resistant to anti-CD33 drug cytotoxicity.

Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis.

Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age.

Microbial-Dependent Recruitment of Immature Myeloid Cells Promotes Intestinal Regeneration.

Background & Aims: The intestinal epithelium functions both in nutrient absorption and as a barrier, separating the luminal contents from a network of vascular, fibroblastic, and immune cells underneath. After injury to the intestine, multiple cell populations cooperate to drive regeneration of the mucosal barrier, including lymphatic endothelial cells (LECs). A population of granulocytic immature myeloid cells (IMCs), marked by Hdc, participate in regeneration of multiple organs such as the colon and central nervous system, and their contribution to intestinal regeneration was investigated.

IL-1β transgenic mouse model of inflammation driven esophageal and oral squamous cell carcinoma.

Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1β transgenic mice, expressing human interleukin (IL)-1β in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett's esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1β-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive.

Novel Insights into the Physiology of Nutrient Sensing and Gut-Brain Communication in Surgical and Experimental Obesity Therapy.

Despite standardized surgical technique and peri-operative care, metabolic outcomes of bariatric surgery are not uniform. Adaptive changes in brain function may play a crucial role in achieving optimal postbariatric weight loss. This review follows the anatomic-physiologic structure of the postbariatric nutrient-gut-brain communication chain through its key stations and provides a concise summary of recent findings in bariatric physiology, with a special focus on the composition of the intestinal milieu, intestinal nutrient sensing, vagal nerve-mediated gastrointestinal satiation signals, circulating hormones and nutrients, as well as descending neural signals from the forebrain.

Loss of -articular cartilage progenitor cells causes osteoarthritis.

Osteoarthritis (OA), which carries an enormous disease burden across the world, is characterised by irreversible degeneration of articular cartilage (AC), and subsequently bone. The cellular cause of OA is unknown. Here, using lineage tracing in mice, we show that the BMP-antagonist () marks a novel chondrogenic progenitor (CP) cell population in the articular surface that generates joint cartilage and subchondral bone during development and adulthood.

Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche.

Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81 PDGFRA trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81 PDGFRA mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands.

Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth.

Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions and associated mechanisms remain unclear. Here, we use primary intestinal organoids modeling homeostatic, injured and tumorigenic epithelia to assess how the fibroblast-derived EGF family ligands neuregulin 1 (NRG1) and epiregulin (EREG) regulate the intestinal epithelium.

The evolving tale of Pol2 function.

DNA replication is complex and highly regulated, and DNA replication errors can lead to human diseases such as cancer. DNA polymerase ε (polε) is a key player in DNA replication and contains a large subunit called POLE, which possesses both a DNA polymerase domain and a 3'-5' exonuclease domain (EXO). Mutations at the EXO domain and other missense mutations on POLE with unknown significance have been detected in a variety of human cancers.

tRNA methylation resolves codon usage bias at the limit of cell viability.

Codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N-methylation of guanosine at position 37 (mG37) on the 3'-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons.

High-Titer Production of the Fungal Anhydrotetracycline, TAN-1612, in Engineered Yeasts.

Antibiotic resistance is a growing global health threat, demanding urgent responses. Tetracyclines, a widely used antibiotic class, are increasingly succumbing to antibiotic resistance; generating novel analogues is therefore a top priority for public health. Fungal tetracyclines provide structural and enzymatic diversity for novel tetracycline analogue production in tractable heterologous hosts, like yeasts, to combat antibiotic-resistant pathogens.

Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells.

Single unit analysis and wide-field imaging reveal alterations in excitatory and inhibitory neurons in glioma.

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events.

Translocation of synergizes with myeloid-derived suppressor cells and contributes to breast carcinogenesis.

Microbial dysbiosis plays an important role in the development of intestinal diseases. Recent studies suggest a link between intestinal bacteria and mammary cancer. Here, we report that female Apc mice infected with exhibited an increased mammary and small/large intestine tumor burden compared with uninfected littermates.

SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes.

SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown.

Colonic healing requires Wnt produced by epithelium as well as Tagln+ and Acta2+ stromal cells.

Although Wnt signaling is clearly important for the intestinal epithelial homeostasis, the relevance of various sources of Wnt ligands themselves remains incompletely understood. Blocking the release of Wnt in distinct stromal cell types suggests obligatory functions of several stromal cell sources and yields different observations. The physiological contribution of epithelial Wnt to tissue homeostasis remains unclear.

Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma.

Glioblastoma is the most prevalent primary malignant brain tumor in adults and is characterized by poor prognosis and universal tumor recurrence. Effective glioblastoma treatments are lacking, in part due to somatic mutations and epigenetic reprogramming that alter gene expression and confer drug resistance. To investigate recurrently dysregulated genes in glioblastoma, we interrogated allele-specific expression (ASE), the difference in expression between two alleles of a gene, in glioblastoma stem cells (GSC) derived from 43 patients.

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis.

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis.