资源环境科技发展态势分析平台

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts(1). Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types(2,3). However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E-2 (PGE(2)). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE(2) drives the expansion omicron f a population of Sca-1(+) reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1(+) cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE(2) promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1(+) cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE(2)-Ptger4. Analyses of patient-derived organoids established that PGE(2)-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE(2)-Ptger4-Yap signalling axis.

Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E-2, which, when disrupted, prevented initiation of intestinal tumours.

Prussian blue analogues (PBAs) are a diverse family of microporous inorganic solids, known for their gas storage ability(1), metal-ion immobilization(2), proton conduction(3), and stimuli-dependent magnetic(4,5), electronic(6) and optical(7) properties. This family of materials includes the double-metal cyanide catalysts(8,9) and the hexacyanoferrate/ hexacyanomanganate battery materials(10,11). Central to the various physical properties of PBAs is their ability to reversibly transport mass, a process enabled by structural vacancies. Conventionally presumed to be random(12,13), vacancy arrangements are crucial because they control micropore-network characteristics, and hence the diffusivity and adsorption profiles(14,15). The long-standing obstacle to characterizing the vacancy networks of PBAs is the inaccessibility of single crystals(16). Here we report the growth of single crystals of various PBAs and the measurement and interpretation of their X-ray diffuse scattering patterns. We identify a diversity of non-random vacancy arrangements that is hidden from conventional crystallographic powder analysis. Moreover, we explain this unexpected phase complexity in terms of a simple microscopic model that is based on local rules of electroneutrality and centrosymmetry. The hidden phase boundaries that emerge demarcate vacancynetwork polymorphs with very different micropore characteristics. Our results establish a foundation for correlated defect engineering in PBAs as a means of controlling storage capacity, anisotropy and transport efficiency.