Cortical organoid-derived models of the melanoma brain metastatic niche enable prioritization of cancer-targeting drugs
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.
Authors
- Robert Zierold (ORCID: https://orcid.org/0000-0003-0292-0970)
- Joachim Wegener (ORCID: https://orcid.org/0000-0001-8554-0150)
- Jann Harberts (ORCID: https://orcid.org/0000-0003-3044-6823)
- Manuel Alexander Friese (ORCID: https://orcid.org/0000-0001-6380-2420)
- Patricia Muschong
- Tobias Naber
- Andrea Zaliani (ORCID: https://orcid.org/0000-0002-1740-8390)
- Susanne Krasemann (ORCID: https://orcid.org/0000-0001-8795-818X)
- Marcel S. Woo (ORCID: https://orcid.org/0000-0002-1306-2708)
- Silvia Materna‐Reichelt
- Christian Conze (ORCID: https://orcid.org/0000-0002-8849-1064)
- Mario Mezler (ORCID: https://orcid.org/0000-0002-7253-0962)
- Melanie Werner‐Klein (ORCID: https://orcid.org/0000-0002-5677-9346)
- Malte Siegmund (ORCID: https://orcid.org/0009-0003-0478-3620)
- Christoph A. Klein (ORCID: https://orcid.org/0000-0001-7128-1725)
- Heiko Siegmund
- Annika Wittich (ORCID: https://orcid.org/0000-0003-0375-226X)
- Undine Haferkamp (ORCID: https://orcid.org/0000-0003-2893-5847)
- Ole Pleß (ORCID: https://orcid.org/0000-0002-1468-316X)
- Katja Evert (ORCID: https://orcid.org/0000-0003-0984-5563)
- Arjen Weller
- Robert H. Blick (ORCID: https://orcid.org/0000-0002-3602-7702)
- Fatima-Zahra Rachad
- Mark Walkenhorst (ORCID: https://orcid.org/0000-0002-2277-9532)
- Nataša Stojanović Gužvić
- Kim Krieg (ORCID: https://orcid.org/0009-0006-5231-5401)
- Pia Kauven
- Dominik Miltner
Institutions
- Leibniz Institute of Virology (LIV) (DE)
- Universität Hamburg (DE)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
- AbbVie (Germany) (DE)
- Hamburg Institut (Germany) (DE)
- University of Regensburg (DE)
Publication Details
- Journal
- Cell Reports Methods
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1016/j.crmeth.2025.101236
- Citations
- 2
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.25