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Cited by 37Colorectal Cancer Treatments and StudiesGenetic factors in colorectal cancerWnt/β-catenin signaling in development and cancer

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

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Reischmann, Nadine, Andrieux, Geoffroy, Griffin, Ricarda, Reinheckel, Thomas, Boerries, Melanie, Brummer, Tilman·2020·Oncogene
DOI 10.1038/s41388-020-01414-9PMC PMC7498370
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Abstract

BRAF V600E confers poor prognosis and is associated with a distinct subtype of colorectal cancer (CRC). Little is known, however, about the genetic events driving the initiation and progression of BRAF V600E mutant CRCs. Recent genetic analyses of CRCs indicate that BRAF V600E often coexists with alterations in the WNT- and p53 pathways, but their cooperation remains ill-defined. Therefore, we systematically compared small and large intestinal organoids from mice harboring conditional BraffloxV600E, Trp53LSL-R172H, and/or Apcflox/flox alleles. Using these isogenic models, we observe tissue-specific differences toward sudden BRAF V600E expression, which can be attributed to different ERK-pathway ground states in small and large intestinal crypts. BRAF V600E alone causes transient proliferation and suppresses epithelial organization, followed by organoid disintegration. Moreover, BRAF V600E induces a fetal-like dedifferentiation transcriptional program in colonic organoids, which resembles human BRAF V600E-driven CRC. Co-expression of p53 R172H delays organoid disintegration, confers anchorage-independent growth, and induces invasive properties. Interestingly, p53 R172H cooperates with BRAF V600E to modulate the abundance of transcripts linked to carcinogenesis, in particular within colonic organoids. Remarkably, WNT-pathway activation by Apc deletion fully protects organoids against BRAF V600E-induced disintegration and confers growth/niche factor independence. Still, Apc-deficient BRAF V600E-mutant organoids remain sensitive toward the MEK inhibitor trametinib, albeit p53 R172H confers partial resistance against this clinically relevant compound. In summary, our systematic comparison of the response of small and large intestinal organoids to oncogenic alterations suggests colonic organoids to be better suited to model the human situation. In addition, our work on BRAF-, p53-, and WNT-pathway mutations provides new insights into their cooperation and for the design of targeted therapies.

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  • MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation.

    “MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation.”

    From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [27]

    The Introduction identifies BRAF mutations as ERK-pathway alterations, and the Discussion reports that BRAFV600E induces dedifferentiation patterns in intestinal organoids. But the paper does not establish that MAPK-driven tumorigenesis generally relies on epithelial dedifferentiation: the Introduction describes dedifferentiation as one of two routes to tumorigenesis, and the study’s model includes additional mutations for transformation. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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  • Gene mutations of BRAF, especially BRAFV600E, and constitutively activated MAPK cascades drive multiple cancers, depriving differentiated features.

    “Gene mutations of BRAF, especially BRAFV600E, and constitutively activated MAPK cascades drive multiple types of cancers, depriving differentiated features through melanoma genesis and intestine/colon carcinogenesis24–27.”

    From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [27]

    The Introduction describes BRAFV600E as a constitutively active oncoprotein in colorectal cancer and links its signaling to reduced intestinal differentiation. The Discussion also reports a dedifferentiation-associated gene-expression pattern in intestinal organoids. These passages support the intestine/colon portion, but do not establish the claim about melanoma or multiple cancer types. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Reischmann, N., Andrieux, G., Griffin, R., Reinheckel, T., Boerries, M., & Brummer, T.
Affiliations
University of Freiburg (DE)
Corresponding author
Brummer, Tilman
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2020-08-13
Volume
39
Issue
38
Pages
6053-6070
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/s41388-020-01414-9
PMC
PMC7498370
OpenAlex
W3048789188
Cited by
37
References
5
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 12 · 2022: 3 · 2021: 5 · 2020: 2
FWCI
2.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (SFB 850 B04, BR 3662/3-1, EXC 294, GSC-4, SFB 850 B07)
  • Bundesministerium für Bildung und Forschung (FKZ 01ZX1708F, FKZ 01ZZ1801B)
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
BrafV600E, colorectal cancer, p53 R172H, APC loss, Wnt signaling, small intestinal organoids, colonic organoids, ERK signaling, trametinib resistance, MEK inhibitors, tumor initiation, anchorage-independent growth, tumor invasion, conditional mouse model
MeSH terms
Animals, Cell Transformation, Neoplastic, Colon, Disease Models, Animal, Humans, Intestine, Small, Models, Biological, Mutation, Neoplasm Invasiveness, Oncogenes, Organoids, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Genes, APC, Computational Biology, Genetic Predisposition to Disease, Gene Expression Profiling, MAP Kinase Signaling System, Tissue Culture Techniques, Proto-Oncogene Proteins B-raf, Mice, Cell Dedifferentiation, Genetic Association Studies

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