Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche

Abstract

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 οf 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.

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation

“…LepR + mesenchymal cells have been shown to possess specific functions in other organs, such as bone marrow 31 , 32 ; however, LepR signaling is not involved in the certain function of this specific cell populations 31 . In colon, recent single-cell RNA-Seq analysis revealed that at least four subsets of fibroblasts are present in the mice colon 4 , 35 . We have not evaluated whether LepR + pericryptal mesenchymal cells are a specific sub-population in the CD34 + population.…”

The mesenchymal context in inflammation, immunity and cancer

“…These homeostatic roles of mesenchymal niches are also suggestive of important roles for the mesenchyme in stem cell function during tissue regeneration and tumorigenesis. Indeed, we recently uncovered a rare pericryptal subpopulation of fibroblasts that controls tumor-initiating intestinal stem cells through paracrine crosstalk involving the PGE 2 -Ptger4-Yap signaling axis 15 . Finally, there are additional specialized functions of MCs that depend on their anatomic location and the properties of individual The mesenchymal context in inflammation, immunity and cancer organs.…”

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

“…Both play a central role in tumor progression, invasion, and metastases and some fibroblast subtypes may play a role tumor initiation (Table 2). A recent study of the murine intestinal mesenchymal niche demonstrated that colorectal cancer initiation was orchestrated by a population of rare peri-cryptal prostaglandin E2 fibroblasts that exert paracrine control over tumor initiating stem cells [63]. CAFs secrete cytokines and growth factors that stimulate tumor growth.…”