Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer
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Abstract
Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.
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Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy
Li, Q., Geng, S., Luo, H., Wang, W., Mo, Y.-Q., Luo, Q., Wang, L., Song, G.-B., Sheng, J.-P., & Xu, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01953-7 · Cited by 546 · see citing works
Xu, Z., Li, W., Dong, X., Chen, Y., Zhang, D., Wang, J. G., Zhou, L., & He, G. (2024) · Clinica Chimica Acta · doi:10.1016/j.cca.2024.119686 · Cited by 69 · see citing works
Current applications of intestinal organoids: a review
Xiang, T., Wang, J., & Li, H. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03768-3 · Cited by 62 · see citing works
Current state and future prospects of spatial biology in colorectal cancer
Carranza, F., Diaz, F. C., Ninova, M., & Velazquez-Villarreal, E. I. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1513821 · Cited by 37 · see citing works
Marteau, V., Nemati, N., Handler, K., Raju, D., Kirchmair, A., Rieder, D., Soto, E. K., Fotakis, G., de Lange, G., Carollo, S., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.12.003 · Cited by 37 · see citing works
Self-citationMeyiah, A., Khan, F. I., Alfaki, D. A., Murshed, K., Raza, A., & Elkord, E. (2025) · Translational Oncology · doi:10.1016/j.tranon.2025.102307 · Cited by 30 · see citing works
Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine
Dakilah, I., Harb, A. A., Abu‐Gharbieh, E., El‐Huneidi, W., Taneera, J., Hamoudi, R., Semreen, M. H., & Bustanji, Y. K. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1324001 · Cited by 23 · see citing works
Advances in precision oncology using patient-derived organoids and functional biomaterials
Singh, H., Mijakovic̀, I., & Singh, P. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1670328 · Cited by 14 · see citing works
Guedes, J., Woldmar, N., Szasz, A. M., Wieslander, E., Pawłowski, K., Horvatovich, P., Malm, J., Szadai, L., Németh, I. B., Marko-Varga, G., et al. (2025) · Journal of Proteomics · doi:10.1016/j.jprot.2025.105493 · Cited by 11 · see citing works
Paraskar, G., Bhattacharya, S., & Anitha, K. (2025) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00686 · Cited by 7 · see citing works
High-dimensional signalling analysis of organoids
Dobric, A., & Tape, C. J. (2025) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2025.102488 · Cited by 6 · see citing works
Studying Immunogenic Cell Death in Human Colorectal Cancer Organoids
Lisandrelli, R., Winkler, M., Trajanoski, Z., & Lamberti, G. (2025) · OncoTargets and Therapy · doi:10.2147/ott.s521346 · Cited by 6 · see citing works
Self-citationProtocol for functional profiling of patient-derived organoids for precision oncology
Nemati, N., Boeck, N., Lamberti, G., Lisandrelli, R., & Trajanoski, Z. (2024) · STAR Protocols · doi:10.1016/j.xpro.2024.102887 · Cited by 6 · see citing works
Self-citationMulti Omics Integration in Colorectal Cancer: From Molecular Insights to Precision Oncology
Liu, Z., Ang, M. Y., & Kue, C. S. (2026) · Cancers · doi:10.3390/cancers18101504 · Cited by 6 · see citing works
NovumRNA: Accurate prediction of non-canonical tumor antigens from RNA sequencing data
Außerhofer, M., Rieder, D., Facciolla, M., Gronauer, R., Lamberti, G., Lisandrelli, R., Pellegatta, S., Trajanoski, Z., & Finotello, F. (2025) · iScience · doi:10.1016/j.isci.2025.113448 · Cited by 3 · see citing works
Self-citationHydrogel design for intestinal organoids: principles governing translational regenerative medicine
Wang, Y., Cao, Z., Li, B., Huang, Y., Wang, G., & Chen, Q. (2025) · Biomaterials Science · doi:10.1039/d5bm00926j · Cited by 3 · see citing works
Heregger, R., Huemer, F., Greil, R., Cañadas-Ortega, M., Posselt, G., Ijsselsteijn, M. E., Plattner, C., Rieder, D., Trajanoski, Z., Krogsdam, A., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1629014 · Cited by 3 · see citing works
Self-citationSingle-cell omics for nutrition research: an emerging opportunity for human-centric investigations
Cassotta, M., Díaz, Y. A., Cianciosi, D., Yang, B., Qi, Z., Chen, G., Villar, S. G., López, L. A. D., Grosso, G., Quiles, J. L., et al. (2025) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2025.2566387 · Cited by 1 · see citing works
Liu, Z., Ang, M. Y., & Kue, C. S. (2026) · doi:10.2196/preprints.95204 · Cited by 1 · see citing works
Single-cell analysis of colon cancer: Novel insight into drug resistance and immunotherapy
Bhamidipati, P., Kocharlakota, S. V., Katneni, V., & Malla, R. R. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-24742-2.00010-1
Analysis of the tumor microenvironment using imaging mass cytometry data
Loncová, Z., Trajanoski, Z., & Rieder, D. (2025) · Methods in cell biology · doi:10.1016/bs.mcb.2025.03.006
Self-citationChoi, H., Choi, S. M., Wang, S., & Chung, J. W. (2025) · Journal of Digestive Cancer Research · doi:10.52927/jdcr.2025.13.2.168
Zhang, P., Tang, X., Akanyibah, F. A., Du, S., & Mao, F. (2025) · Laboratory Investigation · doi:10.1016/j.labinv.2025.104256 · Cited by 1 · see citing works
The Evolving Landscape of Colorectal Organoids in Tissue Engineering: Research Trends and Hotspots
Gan, H., Huang, P., Wang, J., Gao, L., & Li, T. (2026) · Tissue Engineering Part C Methods · doi:10.1177/19373384261417822
Spatial proteomics: technical evolution and applications in cancer research
Tian, X., Huang, D., & Hu, J. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1914317
Wan, K., Tang, K., Wang, L., Tian, Q., Zheng, M., Qian, C., & 刘丽梅 (2026) · MedComm · doi:10.1002/mco2.71028
Ramachandran, P., Chen, C. S. Y., Lee, C. S., Aye, T. T., Kunjukunju, A., Elias, M. H., Mydin, A. R., & Low, T. Y. (2026) · Expert Review of Proteomics · doi:10.1080/14789450.2026.2750129
- Authors
- Plattner, C., Lamberti, G., Blattmann, P., Kirchmair, A., Rieder, D., Loncova, Z., Sturm, G., Scheidl, S., Ijsselsteijn, M., Fotakis, G., Noureen, A., Lisandrelli, R., Böck, N., Nemati, N., Krogsdam, A., Daum, S., Finotello, F., Somarakis, A., Schäfer, A., Wilflingseder, D., Gonzalez Acera, M., Öfner, D., Huber, L. A., Clevers, H., Becker, C., Farin, H. F., Greten, F. R., Aebersold, R., de Miranda, N. F. C. C., & Trajanoski, Z.
- Affiliations
- Innsbruck Medical University (AT)
- ETH Zurich (CH)
- Leiden University Medical Center (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Trajanoski, Zlatko
- ORCID
- Plattner, Christina
- Lamberti, Giorgia
- Blattmann, Peter
- Kirchmair, Alexander
- Rieder, Dietmar
- Sturm, Gregor
- Scheidl, Stefan
- Ijsselsteijn, Marieke
- Fotakis, Georgios
- Noureen, Asma
- Nemati, Niloofar
- Krogsdam, Anne
- Daum, Sophia
- Finotello, Francesca
- Somarakis, Antonios
- Schäfer, Alexander
- Wilflingseder, Doris
- Öfner, Dietmar
- Huber, Lukas A.
- Clevers, Hans
- Becker, Christoph
- Farin, Henner F.
- Greten, Florian R.
- Aebersold, Ruedi
- Trajanoski, Zlatko
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 26
- Issue
- 12
- Pages
- 108399
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC10692669
- OpenAlex
- W4388342914
- Cited by
- 27
- References
- 88
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 6
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (publishedVersion, cc-by)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection
- Funders
- European Research Council
- DFG
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030E-173572)
- Vienna Science and Technology Fund (LS16-025)
- HORIZON EUROPE European Innovation Council
- Innovative Medicines Initiative (imSAVAR 853988)
- Österreichische Krebshilfe Tirol (FF18015)
- ERC (EPIC 786295)
- H2020 EIC FTI (INCITE 964955)
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund (I3291, I3978, T974-B30)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- colorectal cancer, patient-derived organoids, phosphoproteomics, kinase inhibitors, off-target effects, pathway crosstalk, tumor heterogeneity, stemness genes, tumor microenvironment, spatial proteomics, imaging mass cytometry, tumor-immune cell interactions, precision oncology, functional proteomics
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