The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse
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A frequent complication in colorectal cancer (CRC) is regeneration of the tumor after therapy. Here, we report that a gene signature specific for adult intestinal stem cells (ISCs) predicts disease relapse in CRC patients. ISCs are marked by high expression of the EphB2 receptor, which becomes gradually silenced as cells differentiate. Using EphB2 and the ISC marker Lgr5, we have FACS-purified and profiled mouse ISCs, crypt proliferative progenitors, and late transient amplifying cells to define a gene program specific for normal ISCs. Furthermore, we discovered that ISC-specific genes identify a stem-like cell population positioned at the bottom of tumor structures reminiscent of crypts. EphB2 sorted ISC-like tumor cells display robust tumor-initiating capacity in immunodeficient mice as well as long-term self-renewal potential. Taken together, our data suggest that the ISC program defines a cancer stem cell niche within colorectal tumors and plays a central role in CRC relapse.
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Humanized ISC signature scores (Hu-EphB2-ISC; Hu-Lgr5-ISC), but not non-stemness signature scores such as Hu-Late TA and Hu-Proliferation, were significantly associated with tumor progression in 2191 Stage I-IV primary and metastatic CRCs.
“Here we show that humanized ISC signature scores (Hu-EphB2-ISC; Hu-Lgr5-ISC), but not non-stemness signature scores such as Hu-Late TA and Hu-Proliferation [29], were significantly associated with tumor progression in 2191 Stage I-IV (primary) and metastatic CRCs (Fig. 4a).”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [29]
Intestinal stem cell signatures derived from normal crypts identify CRC CSCs and predict disease relapse.
“Intestinal stem cell (ISC) signatures derived from normal crypts have been reported to identify CRC CSCs and predict disease relapse [29].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [29]
Both MEKi resistance and SRC activation signatures were only modestly correlated with the humanized ISC signatures that were reported to identify CRC stem cells and predict disease relapse.
“Moreover, both MEKi resistance and SRC activation signatures were only modestly correlated with the humanized ISC signatures that reported to identify CRC stem cells and predict disease relapse [29] (Fig. 4).”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [29]
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Mertz, D. R., Ahmed, T., & Takayama, S. (2018) · Lab on a Chip · doi:10.1039/c8lc00413g · Cited by 33 · see citing works
LGR5 is associated with tumor aggressiveness in papillary thyroid cancer
Michelotti, G., Jiang, X., Sosa, J. A., Diehl, A. M., & Henderson, B. B. (2015) · Oncotarget · doi:10.18632/oncotarget.5330 · Cited by 31 · see citing works
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- Authors
- Merlos-Suárez, A., Barriga, F. M., Jung, P., Iglesias, M., Céspedes, M. V., Rossell, D., Sevillano, M., Hernando-Momblona, X., da Silva-Diz, V., Muñoz, P., Clevers, H., Sancho, E., Mangues, R., & Batlle, E.
- Affiliations
- Institute for Research in Biomedicine (ES)
- Universitat Autònoma de Barcelona (ES)
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES)
- University Medical Center Utrecht (NL)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Batlle, Eduard
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 8
- Issue
- 5
- Pages
- 511-524
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2157910818
- Cited by
- 934
- References
- 43
- Citations by year
- 2026: 24 · 2025: 38 · 2024: 46 · 2023: 59 · 2022: 67 · 2021: 65 · 2020: 70 · 2019: 64 · 2018: 76 · 2017: 70 · 2016: 67 · 2015: 85 · 2014: 65 · 2013: 62 · 2012: 56
- FWCI
- 31.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, other-oa)
- Funders
- Genentech
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- colorectal cancer, cancer stem cells, intestinal stem cells, EphB2, Lgr5, gene expression signatures, recurrence, transit amplifying cells, tumor-initiating capacity, self-renewal, stem cell niche
- MeSH terms
- Animals, Cell Differentiation, Cell Separation, Cells, Cultured, Colonic Neoplasms, Flow Cytometry, Humans, Intestines, Neoplasm Recurrence, Local, Prognosis, Neoplastic Stem Cells, Mice, Knockout, Gene Expression Regulation, Developmental, Gene Expression Profiling, Cell Surface Extensions, Receptor, EphB3, Receptors, G-Protein-Coupled, Mice, Adult Stem Cells, Stem Cell Niche
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