Multiomics of Colorectal Cancer Organoids Reveals Putative Mediators of Cancer Progression Resulting from SMAD4 Inactivation
Open accessAbstract
The development of metastasis severely reduces the life expectancy of patients with colorectal cancer (CRC).Although loss of SMAD4 is a key event in CRC progression, the resulting changes in biological processes in advanced disease and metastasis are not fully understood.Here, we applied a multiomics approach to a CRC organoid model that faithfully reflects the metastasis-supporting effects of SMAD4 inactivation.We show that loss of SMAD4 results in decreased differentiation and activation of pro-migratory and cell proliferation processes, which is accompanied by the disruption of several key oncogenic pathways, including the TGFβ, WNT, and VEGF pathways.In addition, SMAD4 inactivation leads to increased secretion of proteins that are known to be involved in a variety of pro-metastatic processes.Finally, we show that one of the factors that is specifically secreted by SMAD4-mutant organoids�DKK3�reduces the antitumor effects of natural killer cells (NK cells).Altogether, our data provide new insights into the role of SMAD4 perturbation in advanced CRC.
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Inactivation of SMAD4 effects on transcriptome, proteome and secretome identified three SMAD4-mediated processes that may promote metastasis in advanced colorectal cancer.
“Study of the effects of inactivation of the signal transduction factor SMAD4 on the transcriptome, proteome and secretome led to the identification of three SMAD4-mediated processes that may promote metastasis in individuals with advanced colorectal cancer161.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [161]
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Flagged first, then by citations
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- Authors
- Dijkstra, J. J., Neikes, H. K., Rezaeifard, S., Ma, X., Voest, E. E., Tauriello, D. V. F., & Vermeulen, M.
- Affiliations
- Radboud University Nijmegen (NL)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Vermeulen, Michiel
- ORCID
- Venue
- Journal of Proteome Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2022-11-30
- Volume
- 22
- Issue
- 1
- Pages
- 138-151
- ISSN
- 1535-3893 (ISSN-L)
- 1535-3907
- PMC
- PMC9830641
- OpenAlex
- W4310570044
- Cited by
- 23
- References
- 103
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 5 · 2023: 7
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Proteome Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Radboud Universitair Medisch Centrum
- H2020 European Research Council (771059)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- colorectal cancer, organoids, DKK3, natural killer cells, tumor progression, multi-omics, antitumor immunity, advanced colorectal cancer
- MeSH terms
- Multiomics, Humans, Colorectal Neoplasms, Transforming Growth Factor beta, Cell Line, Tumor, Cell Proliferation, Smad4 Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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