000284364 001__ 284364 000284364 005__ 20260130152439.0 000284364 0247_ $$2doi$$a10.1186/s12943-026-02574-0 000284364 0247_ $$2pmid$$apmid:41580751 000284364 0247_ $$2pmc$$apmc:PMC12849154 000284364 037__ $$aDZNE-2026-00132 000284364 041__ $$aEnglish 000284364 082__ $$a570 000284364 1001_ $$aKomljenovic, Dorde$$b0 000284364 245__ $$aLocal metastatic expansion versus secondary intra-organ dissemination: two causes of neurological death explained by fundamentally different metastatic colonization patterns. 000284364 260__ $$aLondon$$bBiomed Central$$c2026 000284364 3367_ $$2DRIVER$$aarticle 000284364 3367_ $$2DataCite$$aOutput Types/Journal article 000284364 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1769782968_7042 000284364 3367_ $$2BibTeX$$aARTICLE 000284364 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000284364 3367_ $$00$$2EndNote$$aJournal Article 000284364 520__ $$aNeurological failure contributes to 15-50% of deaths in patients with brain metastases, yet the underlying mechanisms remain poorly understood. Clinical causes range from local compression to meningeal metastasis. In this context, a link between infiltrative histopathological growth patterns (HGPs) and meningeal metastasis was recently described and prompted this reverse translation study.We conducted a retrospective postmortem histological assessment and a prospective MRI-based proof-of-concept study to explore neurological decline mechanisms in two experimental brain metastasis models with different HGPs: (i) the non-infiltrative TUBO model, characterized by well-defined tumor borders and a multilayered astrocytic capsule; and (ii) the infiltrative E0771-LG model, exhibiting diffuse infiltration and widespread astrogliosis.In the TUBO model, neurological death resulted from local metastatic expansion compressing vital structures, while the E0771-LG model caused mortality mainly through widespread secondary dissemination. We provide the first direct evidence of contralateral recolonization by secondary metastasis-initiating cells (secMICs), and highlight the high efficiency of secondary spread. Additionally, we show that secMICs exploit distinct anatomical structures to reach distant brain regions, bypassing classical vascular dissemination routes. Notably, the HGP and its associated features are intrinsic to tumor cells and are established early during metastatic colonization.This study identifies the HGP as a potential surrogate for predicting the underlying cause of organ failure in brain metastases. Additionally, it highlights the significant role of secondary dissemination and recolonization in brain metastasis, processes that have been largely overlooked in clinical practice. These findings address a critical knowledge gap and may inform future treatment strategies. 000284364 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0 000284364 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de 000284364 650_7 $$2Other$$aBrain metastasis 000284364 650_7 $$2Other$$aCause of death 000284364 650_7 $$2Other$$aHistological growth pattern 000284364 650_7 $$2Other$$aInfiltration 000284364 650_7 $$2Other$$aLocal metastatic expansion 000284364 650_7 $$2Other$$aMMPI 000284364 650_7 $$2Other$$aMeningeal metastasis 000284364 650_7 $$2Other$$aNeurological decline 000284364 650_7 $$2Other$$aRecolonization 000284364 650_7 $$2Other$$aSecondary dissemination 000284364 650_2 $$2MeSH$$aBrain Neoplasms: secondary 000284364 650_2 $$2MeSH$$aBrain Neoplasms: pathology 000284364 650_2 $$2MeSH$$aBrain Neoplasms: diagnostic imaging 000284364 650_2 $$2MeSH$$aAnimals 000284364 650_2 $$2MeSH$$aHumans 000284364 650_2 $$2MeSH$$aMice 000284364 650_2 $$2MeSH$$aNeoplasm Metastasis 000284364 650_2 $$2MeSH$$aDisease Models, Animal 000284364 650_2 $$2MeSH$$aFemale 000284364 650_2 $$2MeSH$$aRetrospective Studies 000284364 650_2 $$2MeSH$$aMale 000284364 650_2 $$2MeSH$$aMagnetic Resonance Imaging 000284364 650_2 $$2MeSH$$aNervous System Diseases: etiology 000284364 650_2 $$2MeSH$$aNervous System Diseases: pathology 000284364 7001_ $$aBäuerle, Tobias$$b1 000284364 7001_ $$aAlves-de-Lima, Jessica$$b2 000284364 7001_ $$aTrigueros, Laura$$b3 000284364 7001_ $$aDietz, Cara$$b4 000284364 7001_ $$aWinter, Zoltan$$b5 000284364 7001_ $$aAraceli, Tommaso$$b6 000284364 7001_ $$aStrotzer, Quirin$$b7 000284364 7001_ $$aWendl, Christina$$b8 000284364 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b9$$udzne 000284364 7001_ $$aProescholdt, Martin A$$b10 000284364 7001_ $$aHarter, Patrick N$$b11 000284364 7001_ $$aEvert, Katja$$b12 000284364 7001_ $$aPukrop, Tobias$$b13 000284364 7001_ $$00000-0002-4464-8189$$aBlazquez, Raquel$$b14 000284364 773__ $$0PERI:(DE-600)2091373-4$$a10.1186/s12943-026-02574-0$$gVol. 25, no. 1, p. 17$$n1$$p17$$tMolecular cancer$$v25$$x1476-4598$$y2026 000284364 8564_ $$uhttps://pub.dzne.de/record/284364/files/DZNE-2026-00132.pdf$$yRestricted 000284364 8564_ $$uhttps://pub.dzne.de/record/284364/files/DZNE-2026-00132.pdf?subformat=pdfa$$xpdfa$$yRestricted 000284364 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9001539$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b9$$kDZNE 000284364 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0 000284364 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bMOL CANCER : 2022$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2023-05-02T09:06:41Z 000284364 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2023-05-02T09:06:41Z 000284364 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Anonymous peer review$$d2023-05-02T09:06:41Z 000284364 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)9930$$2StatID$$aIF >= 30$$bMOL CANCER : 2022$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2024-12-10 000284364 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2024-12-10 000284364 9201_ $$0I:(DE-2719)1110007$$kAG Haass$$lMolecular Neurodegeneration$$x0 000284364 980__ $$ajournal 000284364 980__ $$aEDITORS 000284364 980__ $$aVDBINPRINT 000284364 980__ $$aI:(DE-2719)1110007 000284364 980__ $$aUNRESTRICTED