Journal Article

DZNE-2026-00132

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Local metastatic expansion versus secondary intra-organ dissemination: two causes of neurological death explained by fundamentally different metastatic colonization patterns.

Komljenovic, D. ; Bäuerle, T. ; Alves-de-Lima, J. ; Trigueros, L. ; Dietz, C. ; Winter, Z. ; Araceli, T. ; Strotzer, Q. ; Wendl, C. ; Brendel, M.DZNE* ; Proescholdt, M. A. ; Harter, P. N. ; Evert, K. ; Pukrop, T. ; Blazquez, R.

2026
Biomed Central London

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Please use a persistent id in citations: doi:10.1186/s12943-026-02574-0

Abstract: Neurological 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.

Keyword(s): Brain Neoplasms: secondary (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Brain Neoplasms: diagnostic imaging (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Neoplasm Metastasis (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Retrospective Studies (MeSH) ; Male (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Nervous System Diseases: etiology (MeSH) ; Nervous System Diseases: pathology (MeSH) ; Brain metastasis ; Cause of death ; Histological growth pattern ; Infiltration ; Local metastatic expansion ; MMPI ; Meningeal metastasis ; Neurological decline ; Recolonization ; Secondary dissemination

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 30 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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