Project EMCR 2012-5473. The Dutch Cancer Society (KWF)


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Paneth cells in intestinal cancer: supporting act or main feature?

Summary

Among the differentiated lineages of the intestinal epithelium, Paneth cells appear to encompass multiple functions: 1. they secrete antimicrobial compounds into the intestinal lumen to control the bacterial flora; 2. they support and are essential for Lgr5+ stem cells by secreting Wnt, Notch and EGF ligands; and 3. upon tissue injury they are able to de-differentiate thus contributing to the regenerative response.

Notably, patients affected by chronic inflammation bowel disease (IBD) syndromes such as ulcerative colitis are characterized by Paneth cell metaplasia, i.e. the “illegitimate” appearance of these cells in the colon where they do not normally reside, likely to result from stem cell reprogramming during the regenerative response of the inflamed intestinal epithelium. IBD patients have an increased colon cancer risk. In this project, we planned to elucidate the functional role of Paneth cells in inflammation and cancer. In particular, our research focus lies on their role as 1. source of secreted niche factors which support self-renewal of the normal and cancer stem cell; and 2. quiescent (C)SCs capable of de- and re-differentiation during chronic inflammation in IBD.

1. To the aim of identifying niche factors secreted by Paneth cells which affect stem cell self-renewal in homeostasis, inflammation and cancer, we employed the ex-vivo ‘mini-gut’ organoid assay in combination with different transgenic/knock-in/knock-out mouse models. During the first two years of the project, particular attention has been devoted to secretory phospholipases and their putative role as stem cell niche factors. The identification of the secretory phospholipase A2 gene (Pla2g2a) as Mom1, i.e. the major modifier of Apc-driven intestinal tumorigenesis, and the fact that Pla2g2a is mainly expressed in Paneth cells provide a solid rationale for this choice. Pla2g2a is involved in the synthesis of arachidonic acid, the rate-limiting substrate for the production of prostaglandins during inflammation. Whereas Pla2g2a expression is mainly limited to the upper GI, another member of the same phospholipase family, Pla2g10, is likely to play a similar role in the colon. By taking advantage of Pla2g2a- and Pla2g10-mutant mice and of the ex-vivo “mini-gut” organoid culture assay, we will assess if and how Paneth cells (and their equivalent in the colon) play rate-limiting roles in tumour formation throughout the intestinal tract.

2. To assess whether a fully differentiated and post-mitotic lineage such as the Paneth cell can paradoxically represent the true quiescent stem cell of the intestinal epithelium under stress conditions, we plan to implement its lineage tracing upon tissue insults such as inflammation, and in cancer. This approach will establish whether the metaplastic Paneth cells in IBD-related colon cancers are essential to support cycling CSCs or if they more actively take part in cancer stemness and/or represent the cell of origin of malignancies associated with chronic inflammation.

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