Expression of R-Spondin 1 in Apc Mice Suppresses Growth of Intestinal Adenomas by Altering Wnt and Transforming Growth Factor Beta Signaling

Background & Aims Mutations in the APC gene and other genes Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify intestinal stem cells. Alterations RSPO have been identified human tumors. We studied effects RSPO1 overexpression ApcMin/+ mutant mice. Methods An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into ApcMin/+mice. Their crypts were isolated cultured as organoids. which incubated with without an inhibitor transforming growth factor beta receptor (TGFBR). Livers collected from mice analyzed by immunohistochemistry. Organoids adenomas quantitative reverse-transcription PCR, single cell RNA sequencing, Results Intestines Apc+/+ had significantly deeper crypts, longer villi, increased EdU labeling, indicating proliferation epithelial cells, comparison given vector. AAV-RSPO1-Fc–transduced also developed fewer smaller tumors survival times. Adenomas showed a rapid increase apoptosis expression target genes, followed reduced messenger RNAs regulated pathway, proliferation, less crypt branching than Addition number adenoma organoids derived suppressed but phosphorylation SMAD2 transcription SMAD. Inhibition TGFBR stimulated restored organoid formation Wnt. The expressing back same level Conclusions Expression increases reduces resulting mouse survival. inhibits their promotes cells retain protein; these reversed TGFB inhibitor. Strategies might be for treatment adenomas.