Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer

iScience, vol. 26, pp. 108399

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.

Authors 30

1. Christina Plattner

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

2. Giorgia Lamberti

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

3. Peter Blattmann

   ETH Zurich · Institute for Molecular Systems Biology

   Affiliation as printed

   Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland

4. Alexander Kirchmair

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

5. Dietmar Rieder

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

6. Zuzana Loncová

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

7. Gregor Sturm

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

8. Stefan J. Scheidl

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria

9. Marieke E. Ijsselsteijn Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands

10. Georgios Fotakis

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

11. Asma Noureen

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

12. Rebecca Lisandrelli

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

13. Nina Böck

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

14. Niloofar Nemati

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

15. Anne Krogsdam

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

16. Sophia Daum

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

17. Francesca Finotello

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

18. Antonios Somarakis Aachen Department of Radiology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands

19. Alexander Schäfer

    ETH Zurich · Institute for Molecular Systems Biology

    Affiliation as printed

    Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland

20. Doris Wilflingseder

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria

21. Miguel Gonzalez Acera

    Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

    Affiliation as printed

    Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany

22. Dietmar Öfner

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria

23. Lukas Alfons Huber

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Cell Biology, Medical University of Innsbruck, 6020 Innsbruck, Austria

24. Hans C. Clevers

    Hubrecht Institute for Developmental Biology and Stem Cell Research

    Affiliation as printed

    Hubrecht Institute, 3584 CT Utrecht, the Netherlands

25. Christoph Becker

    Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

    Affiliation as printed

    Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany

26. Henner F. Farin

    Goethe University Frankfurt · German Cancer Research Center · Georg Speyer Haus · Frankfurt Cancer Institute · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany

    German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership with DKFZ Heidelberg, Frankfurt/Mainz, Germany

    Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany

27. Florian R. Greten

    Goethe University Frankfurt · German Cancer Research Center · Georg Speyer Haus · Frankfurt Cancer Institute · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany

    German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership with DKFZ Heidelberg, Frankfurt/Mainz, Germany

    Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany

28. Ruedi Aebersold

    ETH Zurich · Institute for Molecular Systems Biology

    Affiliation as printed

    Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland

29. Noel F.C.C. de Miranda Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands

30. Zlatko Trajanoski

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria