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Prognostic value of the PrP C -ILK-IDO1 axis in the mesenchymal colorectal cancer subtype
Open accessAbstract
The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrPC is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrPC downstream pathways that may underlie its role in CMS4 CRC. By combining gene set enrichment analyses and gain and loss of function approaches in CRC cell lines, we identify the integrin-linked kinase ILK as a proximal effector of PrPC that mediates its control on the CMS4 phenotype. We further leveraged three independent large CRC cohorts to assess correlations in gene expression pattern with patient outcomes and found that ILK is overexpressed in CMS4 mesenchymal tumors and confers a poor prognosis, especially when combined with high expression of the PrPC encoding gene PRNP. Of note, we discovered that the PrPC-ILK signaling axis controls the expression and activity of the tryptophan metabolizing enzyme indoleamine 2,3 dioxygenase IDO1, a key player in immune tolerance. In addition, we monitored alterations in the levels of tryptophan and its metabolites of the kynurenine pathway in the plasma of metastatic CRC patients (n = 325) and we highlight their prognostic value in combination with plasma PrPC levels. Thus, the PrPC-ILK-IDO1 axis plays a key role in the mesenchymal subtype of CRC. PrPC and IDO1-targeted strategies may represent new avenues for patient stratification and treatment in CRC.
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“we introduced PrPC, a plasma membrane-tethered protein endowed with the capacity to participate in signal transduction events (38), as a key protagonist of CMS4 colon cancer, controlling the expression of many CMS4-specific genes in colon cancer cells through diverse signaling intermediates (35, 39).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [39]
In the citing paper
“Another effector is the integrin linked kinase (ILK), which we found to be overexpressed in CMS4 colon cancer and to act as a relay downstream from PrPC to activate YAP/TAZ signaling (39).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [39]
In the citing paper
“Regarding the immunotolerant CMS4 TME, we posit an involvement of TGFβ (56) and Kynurenine (57), both produced by cancer cells under the control of PrPC (35, 39)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [39]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
The consensus molecular subtypes of colorectal cancer
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Self-citationTGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
Tauriello, D. V. F., Palomo-Ponce, S., Stork, D., Berenguer-Llergo, A., Badia-Ramentol, J., Iglesias, M., Sevillano, M., Ibiza, S., Cañellas, A., Hernando-Momblona, X., et al. (2018) · Nature · doi:10.1038/nature25492 · Cited by 1,851
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Self-citationIDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance
Munn, D. H., & Mellor, A. L. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.01.002 · Cited by 1,081
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
Dienstmann, R., Vermeulen, L., Guinney, J., Kopetz, S., Tejpar, S., & Tabernero, J. M. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.126 · Cited by 1,070
Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D. V. F., Iglesias, M., Céspedes, M. V., Sevillano, M., Nadal, C., Jung, P., Zhang, X. H.-F., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.013 · Cited by 1,060
ILK, PINCH and parvin: the tIPP of integrin signalling
Legate, K. R., Montañez, E., Kudlacek, O., & Füssler, R. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1789 · Cited by 678
Brandacher, G., Perathoner, A., Ladurner, R., Schneeberger, S., Obrist, P., Winkler, C., Werner, E. R., Werner-Felmayer, G., Weiss, H. G., G√∂bel, G., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1966 · Cited by 614
Becht, E., de Reyniès, A., Giraldo, N. A., Pilati, C., Buttard, B., Lacroix, L., Selves, J., Sautès-Fridman, C., Laurent-Puig, P., & Fridman, W. H. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2879 · Cited by 590
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Silva, J. L., Foguel, D., Ferreira, V. F., Vieira, T. C. R. G., Marques, M. A., Ferretti, G. D. S., Outeiro, T. F., Cordeiro, Y., & de Oliveira, G. A. P. (2023) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00131 · Cited by 86
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Self-citationYang, Q., Hao, J., Chi, M., Wang, Y., Xin, B., Huang, J., Lu, J., Li, J., Sun, X., Li, C., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2055703 · Cited by 42
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Metadata
- Authors
- Ghazi, A., Le Corre, D., Pilati, C., Taieb, J., Aparicio, T., Didelot, A., Dedhar, S., Mulot, C., Le Malicot, K., Djouadi, F., de Reynies, A., Launay, J.-M., Laurent-Puig, P., & Mouillet-Richard, S.
- Affiliations
- Inserm (FR)
- INSERM, Sorbonne Université, Université de Paris
- Université Paris Cité (FR)
- BC Cancer Agency (CA)
- Epicad Inserm, Université de Bourgogne et and Franche Comté
- Ligue Nationale Contre Le Cancer
- F. Hoffmann-La Roche AG (CH)
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2021-01
- Volume
- 10
- Issue
- 1
- Pages
- 1940674-1940674
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC8244775
- OpenAlex
- W3174249227
- Cited by
- 21
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 2
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- OncoImmunology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Cancéropôle Ile de France
- Association pour la recherche sur le cancer (PJA 20171206220)
- Institut National de la Santé et de la Recherche Médicale (NA)
- Fondation ARCAD (NA)
- Labex Immuno-Oncology (NA)
- siric carpem (INCa-DGOS-INSERM-12561)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- colorectal cancer, cellular prion protein, integrin-linked kinase, IDO1, tryptophan metabolism, kynurenine pathway, prognostic factors, plasma biomarkers, tumor immune tolerance, prion protein gene, patient stratification
- MeSH terms
- Prion Proteins, Scaffold Protein ILK, Humans, Prognosis, Colorectal Neoplasms, Protein Serine-Threonine Kinases, Indoleamine-Pyrrole 2,3,-Dioxygenase
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