Details

Autor(en) / Beteiligte

• Hilkens, John
• Timmer, Nikki C
• Boer, Mandy
• Ikink, Gerjon J
• Schewe, Matthias
• Sacchetti, Andrea
• Koppens, Martijn A J
• Song, Ji-Ying
• Bakker, Elvira R M

Titel

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.