2. Academic Validation
  3. Cortical organoid-derived models of the melanoma brain metastatic niche enable prioritization of cancer-targeting drugs

Cortical organoid-derived models of the melanoma brain metastatic niche enable prioritization of cancer-targeting drugs

  • Cell Rep Methods. 2025 Dec 15;5(12):101236. doi: 10.1016/j.crmeth.2025.101236.
Kim Krieg 1,  Silvia Materna-Reichelt 2,  Tobias Naber 3,  Fatima-Zahra Rachad 1,  Pia Kauven 1,  Arjen Weller 1,  Undine Haferkamp 1,  Annika Wittich 1,  Andrea Zaliani 1,  Marcel S Woo 4,  Mark Walkenhorst 4,  Malte Siegmund 5,  Jann Harberts 6,  Robert Zierold 5,  Robert Blick 5,  Christian Conze 7,  Patricia Muschong 8,  Dominik Miltner 8,  Manuel A Friese 4,  Mario Mezler 8,  Heiko Siegmund 9,  Katja Evert 9,  Susanne Krasemann 10,  Nataša Stojanović Gužvić 2,  Christoph A Klein 11,  Melanie Werner-Klein 12,  Joachim Wegener 3,  Ole Pless 13
Affiliations

Affiliations

  • 1 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany.
  • 2 Fraunhofer Institute for Toxicology and Experimental Medicine ITEM-R, Division of Personalized Tumor Therapy, 93053 Regensburg, Germany.
  • 3 Fraunhofer Institute for Electronic Microsystems and Solid-State Technologies EMFT, Cell-based Sensor Technology, 93053 Regensburg, Germany; Institute for Analytical Chemistry, Chemo- & Biosensors, University of Regensburg, 93053 Regensburg, Germany.
  • 4 Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
  • 5 Center for Hybrid Nanostructures, University of Hamburg, 22761 Hamburg, Germany.
  • 6 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany; Center for Hybrid Nanostructures, University of Hamburg, 22761 Hamburg, Germany.
  • 7 Technology Platform Microscopy and Image Analysis (TP MIA), Leibniz Institute of Virology, 20251 Hamburg, Germany.
  • 8 AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, Germany.
  • 9 Institute for Pathology, University of Regensburg, 93053 Regensburg, Germany.
  • 10 Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Experimental Pathology Core Facility, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 11 Fraunhofer Institute for Toxicology and Experimental Medicine ITEM-R, Division of Personalized Tumor Therapy, 93053 Regensburg, Germany; Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
  • 12 Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
  • 13 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany. Electronic address: [email protected].
PMID: 41240911 DOI: 10.1016/j.crmeth.2025.101236
Abstract

Effective systemic therapies against brain metastases are severely limited. To understand and target vulnerabilities of human metastases in a brain niche context, we developed reproducible melanoma brain metastasis (MBM) models for metastasis-integrating drug screening. We co-cultured A375 melanoma cells or tumor regional lymph node-derived disseminated Cancer cells (DCCs) in close proximity with human induced pluripotent stem cell-derived cortical organoids (hCOs). In these, RNA Sequencing revealed an upregulation of metastasis-associated features. First, A375 cells and DCCs were screened against an anti-cancer library containing 315 compounds. Hits were ranked by neurotoxicity, central nervous system permeation, and anti-DCC efficacy. Only a minority of hits effectively targeted A375-MBMs, with the first-in-class XPO1 inhibitor selinexor emerging as top hit. Selinexor also demonstrated efficacy in DCC-MBM models and low toxicity on hCOs, suggesting a promising therapeutic window in clinically applied doses. Collectively, the MBM model provides a tool for identifying candidate therapies counteracting metastatic progression.

Keywords

CP: cancer biology; CP: stem cell; XPO1; assay development; cortical organoids; disseminated cancer cells; drug discovery; high-throughput screening; melanoma brain metastases; personalized medicine; preclinical cancer model; selinexor.

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