iScience (Dec 2023)
Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer
- Christina Plattner,
- Giorgia Lamberti,
- Peter Blattmann,
- Alexander Kirchmair,
- Dietmar Rieder,
- Zuzana Loncova,
- Gregor Sturm,
- Stefan Scheidl,
- Marieke Ijsselsteijn,
- Georgios Fotakis,
- Asma Noureen,
- Rebecca Lisandrelli,
- Nina Böck,
- Niloofar Nemati,
- Anne Krogsdam,
- Sophia Daum,
- Francesca Finotello,
- Antonios Somarakis,
- Alexander Schäfer,
- Doris Wilflingseder,
- Miguel Gonzalez Acera,
- Dietmar Öfner,
- Lukas A. Huber,
- Hans Clevers,
- Christoph Becker,
- Henner F. Farin,
- Florian R. Greten,
- Ruedi Aebersold,
- Noel F.C.C. de Miranda,
- Zlatko Trajanoski
Affiliations
- Christina Plattner
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Giorgia Lamberti
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Peter Blattmann
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland
- Alexander Kirchmair
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Dietmar Rieder
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Zuzana Loncova
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Gregor Sturm
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Stefan Scheidl
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Marieke Ijsselsteijn
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Georgios Fotakis
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Asma Noureen
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Rebecca Lisandrelli
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Nina Böck
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Niloofar Nemati
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Anne Krogsdam
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Sophia Daum
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Francesca Finotello
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Antonios Somarakis
- Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Alexander Schäfer
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland
- Doris Wilflingseder
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Miguel Gonzalez Acera
- Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Lukas A. Huber
- Biocenter, Institute of Cell Biology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Hans Clevers
- Hubrecht Institute, 3584 CT Utrecht, the Netherlands
- Christoph Becker
- Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany
- Henner F. Farin
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany; 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
- Florian R. Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany; 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
- Ruedi Aebersold
- Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland
- Noel F.C.C. de Miranda
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
- Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 12
p. 108399
Abstract
Summary: 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.
