Cited by 23TGF-β signaling in diseasesCancer Cells and MetastasisChromatin Remodeling and Cancer

Multiomics of Colorectal Cancer Organoids Reveals Putative Mediators of Cancer Progression Resulting from SMAD4 Inactivation

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Dijkstra, Jelmer J., Neikes, Hannah K., Rezaeifard, Somayeh, Ma, Xuhui, Voest, Emile E., Tauriello, Daniele V. F., Vermeulen, Michiel·2023·Journal of Proteome Research

Abstract

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.”

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Research works printed but not linked: 2

  1. Wickham H. ggplot2: Elegant Graphics for Data Analysis; Springer-Verlag: New York, 2016.
  2. Beck S. E.; Jung B. H.; Fiorino A.; et al. Bone morphogenetic protein signaling and growth suppression in colon cancer. Am. J. Physiol. – Gastrointest. Liver Physiol. 2006, 291, G135– G145. 10.1152/ajpgi.00482.2005. 16769811 PMC4138725 · DOI

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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
Venue
Journal of Proteome Research
Published
2022-11-30
Volume
22
Issue
1
Pages
138-151
ISSN
  • 1535-3893 (ISSN-L)
  • 1535-3907
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
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

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