Α new collaborative study published in ‘Nature’ by George Kollias’ lab at BSRC Fleming and University of Athens Medical School, and Richard Flavell’s lab at Yale University School of Medicine, provides the first definitive in vivo evidence that the mesenchymal microenvironment of intestinal stem cells controls tumor initiation in the intestine. The study reveals a mechanism whereby a population of cyclooxygenase-2 (Cox-2)-expressing fibroblasts acts through the druggable prostaglandin E2 (PGE2)/Ptger4/Yap signaling axis to exert a paracrine control over tumor initiating stem cells, thereby driving colon tumorigenesis in the presence of oncogenic mutations.
The mesenchymal microenvironment is increasingly recognized as an important host modulator both in health and disease. Tumor initiation in the intestine depends on the competition between mutant and normal epithelial stem cells in crypts. Intestinal stem cells are closely associated with a mesenchymal cell-network. However, the presence of a functional dialog between these different cell types, which could tip the balance between homeostasis and tumor progression, has not been addressed definitively.
To study the contribution of the mesenchymal niche on mutant stem cell dominance and tumorigenesis, the researchers adopted a single cell transcriptomic analysis approach leading to the identification of a rare population of fibroblasts, located around part of the crypts and in close proximity to the stem cell zone, which constitutively express Cox-2 and process arachidonic acid into PGE2. Interestingly, arachidonic acid pathway and Cox-2 were previously associated with colorectal cancer; however their cellular and molecular mechanisms of action were unknown. An initial finding of the study was that fibroblast-specific ablation of Cox-2 led to significant reduction of tumor load in two different models of sporadic tumorigenesis, while fibroblast-specific Cox-2 expression was necessary for tumor initiation. These observations inspired a subsequent series of elaborate in vitro and in vivo experiments indicating that PGE2-secreting fibroblasts act through Ptger4 receptor on their neighboring stem cells to activate a pro-tumorigenic Yap program on them, driving their expansion and the formation of intestinal tumors. The initial in vivo observations of the study were performed in Kollias lab by Manolis Roulis and Aimilios Kaklamanos (the two first co-authors of the study). Manolis Roulis in collaboration with the other researchers in the paper, completed the delineation of the mechanism of action in Flavell’s lab where he moved for post-doctoral studies.
Taken together, this study draws a more complete picture of our understanding of cancer pathogenesis whereas mesenchymal fibroblastic cells engage in a cellular dialog with mutated stem cells, which is critical for tumor initiation. Importantly, it should also be noted that in humans the pharmacological inhibition of Cox-2 has a significant preventive effect against colorectal cancer although the mechanism was so far unknown; however due to cardiovascular adverse effects Cox-2 inhibitors cannot be used for treatment. The novel molecular and cellular pathway revealed in the studies could provide alternative therapeutic targets for colorectal cancer with fewer side effects.
The research groups of Vasiliki Koliaraki and Vassilis Aidinis from Fleming also contributed to this study.
Manolis Roulis, Aimilios Kaklamanos, Marina Schernthanner, Piotr Bielecki, Jun Zhao, Eleanna Kaffe, Laura-Sophie Frommelt, Rihao Qu, Marlene S. Knapp, Ana Henriques, Niki Chalkidi, Vasiliki Koliaraki, Jing Jiao, J. Richard Brewer, Maren Bacher, Holly N. Blackburn, Xiaoyun Zhao, Richard M. Breyer, Vassilis Aidinis, Dhanpat Jain, Bing Su, Harvey R. Herschman, Yuval Kluger, George Kollias & Richard Flavell. Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche. Nature (2020).