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

doi:10.1016/j.isci.2023.108399

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

iScience. 2023 Nov 4;26(12):108399. doi: 10.1016/j.isci.2023.108399. eCollection 2023 Dec 15.

Authors

Christina Plattner¹, Giorgia Lamberti¹, Peter Blattmann², Alexander Kirchmair¹, Dietmar Rieder¹, Zuzana Loncova¹, Gregor Sturm¹, Stefan Scheidl³, Marieke Ijsselsteijn⁴, Georgios Fotakis¹, Asma Noureen¹, Rebecca Lisandrelli¹, Nina Böck¹, Niloofar Nemati¹, Anne Krogsdam¹, Sophia Daum¹, Francesca Finotello¹, Antonios Somarakis⁵, Alexander Schäfer², Doris Wilflingseder⁶, Miguel Gonzalez Acera⁷, Dietmar Öfner³, Lukas A Huber⁸, Hans Clevers⁹, Christoph Becker⁷, Henner F Farin^{10

11

12}, Florian R Greten^{10

11

12}, Ruedi Aebersold², Noel F C C de Miranda⁴, Zlatko Trajanoski¹

Affiliations

¹ Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
² Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8092 Zurich, Switzerland.
³ Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁴ Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁵ Department of Radiology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁶ Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁷ Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany.
⁸ Biocenter, Institute of Cell Biology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
⁹ Hubrecht Institute, 3584 CT Utrecht, the Netherlands.
¹⁰ Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
¹¹ Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany.
¹² German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership with DKFZ Heidelberg, Frankfurt/Mainz, Germany.

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.

Keywords: Cancer; Cancer systems biology; Proteomics.