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RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis
Ist Teil von
Gut, 2017-06, Vol.66 (6), p.1095
Ort / Verlag
England
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (
or
mutations. However, a subset of human colon tumours harbour, mutually exclusive with
and
mutations, gene fusions in
or
leading to enhanced expression of these R-spondin genes. This suggested that
activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in
-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel.
We generated a conditional
transgenic mouse model in which the
transgene is expressed upon Cre activity. Cre is provided by cross-breeding with
-GFP-Cre
mice.
Upon in vivo
expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5
stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4
cells, thus promoting both intestinal stem cell and niche compartments. Wnt/β-catenin signalling was modestly increased upon
expression and mutant
synergised with
in hyperplastic growth.
We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring
fusions.