학술논문

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.
Document Type
Academic Journal
Author
Plattner C; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Lamberti G; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Blattmann P; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland.; Kirchmair A; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Rieder D; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Loncova Z; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Sturm G; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Scheidl S; Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Ijsselsteijn M; Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.; Fotakis G; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Noureen A; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Lisandrelli R; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Böck N; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Nemati N; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Krogsdam A; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Daum S; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Finotello F; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Somarakis A; Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.; Schäfer A; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland.; Wilflingseder D; Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Gonzalez Acera M; Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.; Öfner D; Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Huber LA; Biocenter, Institute of Cell Biology, Medical University of Innsbruck, 6020 Innsbruck, Austria.; Clevers H; Hubrecht Institute, 3584 CT Utrecht, the Netherlands.; Becker C; Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.; Farin HF; 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.; Greten FR; 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.; Aebersold R; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland.; de Miranda NFCC; Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.; Trajanoski Z; Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 101724038 Publication Model: eCollection Cited Medium: Internet ISSN: 2589-0042 (Electronic) Linking ISSN: 25890042 NLM ISO Abbreviation: iScience Subsets: PubMed not MEDLINE
Subject
Language
English
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.
Competing Interests: H.C. is an inventor on several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. H.C. is currently head of pharma Research Early Development (pRED) at Roche. H.C. holds several patents on organoid technology. Their application numbers, followed by their publication numbers (if applicable), are as follows: PCT/NL2008/050543, WO2009/022907; PCT/NL2010/000017, WO2010/090513; PCT/IB2011/002167, WO2012/014076; PCT/IB2012/052950, WO2012/168930; PCT/EP2015/060815, WO2015/173425; PCT/EP2015/077990, WO2016/083613; PCT/EP2015/077988, WO2016/083612; PCT/EP2017/054797, WO2017/149025; PCT/EP2017/065101, WO2017/220586; PCT/EP2018/086716, n/a; and GB1819224.5, n/a.
(© 2023 The Author(s).)