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, Proescholdt MA, Harter PN, Evert K, Pukrop T, Blazquez R (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Molecular Cancer BioMed Central

Book Volume: 25

Article Number: 17

Journal Issue: 1

DOI: 10.1186/s12943-026-02574-0

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Authors with CRIS profile

Dorde Komljenovic Institute of Radiology Tobias Bäuerle Professur für Multimodale Bildgebung in der präklinischen Forschung Zoltan Winter Department of Anaesthesiology

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Klinikum der Universität München (LMU Klinikum) DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universität Regensburg DE Germany (DE)

How to cite

APA:

Komljenovic, D., Bäuerle, T., Alves-de-Lima, J., Trigueros, L., Dietz, C., Winter, Z.,... Blazquez, R. (2026). Local metastatic expansion versus secondary intra-organ dissemination: two causes of neurological death explained by fundamentally different metastatic colonization patterns. Molecular Cancer, 25(1). https://doi.org/10.1186/s12943-026-02574-0

MLA:

Komljenovic, Dorde, et al. "Local metastatic expansion versus secondary intra-organ dissemination: two causes of neurological death explained by fundamentally different metastatic colonization patterns." Molecular Cancer 25.1 (2026).

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