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The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche. Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.

Background Large clonal populations of cells bearing PIG - A mutations are the sine qua non of PNH, but the PIG - A mutation itself is insufficient for clonal expansion. The association between PNH and aplastic anemia supports the immune escape model, but not all PNH patients demonstrate a history of aplasia; therefore, second genetic hits driving clonal expansion have been postulated. Based on the previous identification of JAK2 mutations in patients with a myeloproliferative/PNH overlap syndrome, we considered TET2 as a candidate gene in which mutations might be contributing to clonal expansion. Methods Here we sequenced the TET2 and JAK2 genes in 19 patients with large PNH clones. Results We found one patient with a novel somatic nonsense mutation in TET2 in multiple hematopoietic lineages, which was detectable upon repeat testing. This patient has had severe thromboses and has relatively higher peripheral blood counts compared with the other patients—but does not have other features of a myeloproliferative neoplasm. Conclusions We conclude that mutations in TET2 may contribute to clonal expansion in exceptional cases of PNH.

Tu et al. show that Tff2 corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. Tff2 corpus cells are TA progenitors that give rise to secretory cells. Tff2 progenitors, not chief cells, are the primary source of SPEM after injury. Kras-mutant Tff2 progenitors progress directly to dysplasia, bypassing metaplasia. Multi-omics analysis reveals distinct trajectories for SPEM and gastric cancer. Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using knockin mice, we identified highly proliferative Tff2 progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2 corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2 progenitors abrogated SPEM formation, while genetic ablation of GIF chief cells enhanced SPEM formation from Tff2 progenitors. In response to infection, Tff2 progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of Kras mutations in Tff2 progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2 progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine -mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified upregulation, and then verified its upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the mutation and β-adrenergic signaling, in part, through the MAPK pathway. culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the model, knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In mice, knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC , we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP CXCR4 tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8 T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4 LOX-1 subset are inversely correlated with the TFF2 level and CD8 T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.