Seminar: Prof. Riccardo Fodde

Multi-tasking Paneth(-like) cells: quiescent cancer stem cells, niche factors, and colon cancer susceptibility modifiers.

Date:
4 September 2014 00:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Multi-tasking Paneth(-like) cells: quiescent cancer stem cells, niche factors, and colon cancer susceptibility modifiers.
Speaker(s):

Riccardo Fodde, Professor of Experimental Pathology, Josephine Nefkens Institute of the Erasmus Medical Center in Rotterdam.

Host(s):

Prof. H. Stunnenberg, Dept. of Molecular Biology, RIMLS, Nijmegen.

04-09-2014 00:00:00Europe/AmsterdamMulti-tasking Paneth(-like) cells: quiescent cancer stem cells, niche factors, and colon cancer susceptibility modifiers. Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

FoddePaneth cells represent one of the five cell lineages of the small intestinal epithelium earmarked by characteristic granules containing lysozyme and other antimicrobial compounds secreted into the intestinal lumen to control the bacterial flora. Paneth cells are localized in the lower third of the crypt of Lieberkühn where they also provide physical support and essential though yet unknown niche signals to the rapidly cycling Lgr5+ stem cells. Furthermore, Paneth cells, notwithstanding their fully differentiated and post-mitotic identity, are characterized by nuclear b-catenin and constitutive activation of the canonical Wnt signal transduction pathway known to be active in many stem cell niches where it regulates the homeostatic equilibrium between self-renewal and differentiation. Notably, Paneth cells are exclusively found in the upper intestinal tract though not in the colon. Our laboratory has shown that Paneth cells represent bona fide label-retaining cells and are likely to act as quiescent stem cells in the intestinal niche capable of underlying regeneration upon tissue insults. More recently, this original observation was confirmed by means of lineage tracing pointing at Paneth cell and their secretory progenitors as the quiescent stem cells of the upper GI tract.

As for their 'niche' role, we show that a Paneth-specific gene family, namely the secreted phospholipases, one of which (Pla2g2a) was previously identified as the major modifier of Apc-driven intestinal tumorigenesis in the mouse (Mom1, modifier of Min), plays a major functional role within the crypt of Lieberkühn as stem cell niche factors. Notably, secreted phospholipases such as Pla2g2a exert both an inhibitory and stimulatory effect on intestinal stemness (expressed as the capacity of forming mini-gut organoids in vitro) under homeostatic and inflammatory conditions, respectively. Furthermore, we have identified a Paneth-like cell type in the colonic epithelium capable of supporting rapidly cycling (Lgr5+) stem cells in mini-gut organoid formation. Notably, these Paneth-like cells of the large intestine were shown to specifically express a distinct secretory phospholipase (Pla2g10). As for Pla2g2a (Mom1) in the small intestine, Pla2g10-/- mice show increased susceptibility to colon cancer especially in the context of inflammation. We are currently investigating the role played by the human homologous gene (PLA2G10) as a candidate modifier gene in IBD-associated colon cancer.    

 

 



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