Cortical organoid-derived models of the melanoma brain metastatic niche enable prioritization of cancer-targeting drugs PMID: 41240911

ADC Targets in Oncology

2026-04-10

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

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].

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.