SMAD4 Suppresses WNT-Driven Dedifferentiation and Oncogenesis in the Differentiated Gut Epithelium

Abstract

The cell of origin of colon cancer is typically thought to be the resident somatic stem cells, which are immortal and escape the continual cellular turnover characteristic of the intestinal epithelium. However, recent studies have identified certain conditions in which differentiated cells can acquire stem-like properties and give rise to tumors. Defining the origins of tumors will inform cancer prevention efforts as well as cancer therapies, as cancers with distinct origins often respond differently to treatments. We report here a new condition in which tumors arise from the differentiated intestinal epithelium. Inactivation of the differentiation-promoting transcription factor SMAD4 in the intestinal epithelium was surprisingly well tolerated in the short term. However, after several months, adenomas developed with characteristics of activated WNT signaling. Simultaneous loss of SMAD4 and activation of the WNT pathway led to dedifferentiation and rapid adenoma formation in differentiated tissue. Transcriptional profiling revealed acquisition of stem cell characteristics, and colabeling indicated that cells expressing differentiated enterocyte markers entered the cell cycle and reexpressed stem cell genes upon simultaneous loss of SMAD4 and activation of the WNT pathway. These results indicate that SMAD4 functions to maintain differentiated enterocytes in the presence of oncogenic WNT signaling, thus preventing dedifferentiation and tumor formation in the differentiated intestinal epithelium. This work identifies a mechanism through which differentiated cells prevent tumor formation by suppressing oncogenic plasticity. .

SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis

“…CTNNB1 (also known as β-catenin), for instance, is induced by SMAD4 in human Tenon's capsule fibroblasts; this factor is involved in the promotion of cell proliferation and activation by TGF-β signaling pathways 9 . Conversely, nuclear β-catenin and other signature genes of the Wnt signaling pathway are upregulated in epithelial tumors harboring Smad4-KO 49 . However, the mechanism by which SMAD4 directly regulates the components of the Wnt signaling pathway had been unclear.…”

“…The TGF-β signaling pathway is multifunctional, and controls many biological functions related to development and diseases, usually via interactions with other important signaling pathways such as BMP, ERK, Hippo, JAK/STAT, Notch, NF-κB, MAPK, and Wnt signaling pathways 9,47,48 . In particular, crosstalk between the TGF-β and Wnt signaling pathways has been extensively studied 49,50 . However, the regulatory relationship between these pathways in mammalian ovaries, and the specific mechanism involved in their interactions, remain largely unknown 51,52 .…”

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

“…It has been shown that blocking BMP signalling leads to the formation of ectopic crypt and epithelial hyperplasia in transgenic mice, with histology resembling human Juvenile Polyposis commonly caused by BMPR1A or SMAD4 mutations 41 42. More recently, two transgenic mouse models demonstrated that inhibition of the BMP pathway by GREM1 hyperexpression (a BMP inhibitor)43 or SMAD4 inactivation44 can resensitise mature villus cells to form ectopic crypts, and concurrent activation of Wnt signalling has a synergistic effect in initiating neoplasia. A recent study has attempted to re-create the traditional serrated adenoma from normal human colon organoids through CRISPR-Cas9 chromosome engineering of R-spondin fusion, TP53 mutation and BRAF mutation 22.…”

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

“…Both populations have been linked to cancer generation in mouse models ( 24 , 26 , 27 ). In colon cancers, recent studies in mice have shown that even differentiated intestinal epithelial cells can be potential CSCs ( 28 ). The fact that adult differentiated cells, tissue resident stem cells or their progeny can promote tumor generation has also been shown in the liver.…”