ArticleCancer research2018
SMAD4 Suppresses WNT-Driven Dedifferentiation and Oncogenesis in the Differentiated Gut Epithelium.
Article in Cancer research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 80 citations in OpenAlex.
- Review
- Dedifferentiation-driven oncogenic stemness promotes tumor-sustaining adaptability in the intestinal epithelium.Cell death & disease · 2026Article
- Fetal reversion from diverse lineages sustains the intestinal stem cell pool and confers stress resilience.Communications biology · 2026Article
- BMP signalling in colorectal cancer: losing the yin to WNTs yang.The Journal of pathology · 2025Review
- Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists.Cancers · 2025Article
- Carcinogenesis trajectories.Frontiers in cell and developmental biology · 2025Article
- Epithelial-specific loss of Smad4 alleviates the fibrotic response in an acute colitis mouse model.Life science alliance · 2024Article
- Cancer, metastasis, and the epigenome.Molecular cancer · 2024Review
- Cancer stem cells: advances in knowledge and implications for cancer therapy.Signal transduction and targeted therapy · 2024Review
- Dynamic RNA polymerase II occupancy drives differentiation of the intestine under the direction of HNF4.Cell reports · 2024Article
- Initiation of Cancer: The Journey From Mutations in Somatic Cells to Epigenetic Changes in Tissue-resident VSELs.Stem cell reviews and reports · 2024Review
- Drug repurposing for cancer therapy.Signal transduction and targeted therapy · 2024Review
- Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma.Biomedicines · 2024Article
- Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance.Cancer metastasis reviews · 2024Review
- scRNA-seq revealed high stemness epithelial malignant cell clusters and prognostic models of lung adenocarcinoma.Scientific reports · 2024Article
- Epigenetic regulation of mRNA mediates the phenotypic plasticity of cancer cells during metastasis and therapeutic resistance (Review).Oncology reports · 2024Review
- In Vitro Organoid-Based Assays Reveal SMAD4 Tumor-Suppressive Mechanisms for Serrated Colorectal Cancer Invasion.Cancers · 2023Article
- Colorectal Cancer Stem Cells and Targeted Agents.Pharmaceutics · 2023Review
- Dynamic RNA Polymerase II Recruitment Drives Differentiation of the Intestine under the direction of HNF4.bioRxiv : the preprint server for biology · 2023Article
- Transcriptomic analysis reveals a tissue-specific loss of identity during ageing and cancer.BMC genomics · 2023Article
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.