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Integrating Extracellular Matrix Dynamics and Membrane-Associated Signaling: The Role of Clusterin-LRP1 Network in Cancer Cell Migration and Tumor Progression
by
, , and
Alessia Ciringione
1
,
Federica Rizzi
1,*,
Sylvia Mangani
2,
Zoi Piperigkou
2
and
Nikos Karamanos
2,*
1
Laboratory of Biochemistry, Molecular Biology and Oncometabolism, Department of Medicine and Surgery, University of Parma, Via Volturno 39, 43125 Parma, Italy
2
Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Department of Chemistry, University of Patras, 26504 Patras, Greece
*
Authors to whom correspondence should be addressed.
Cancers 2026, 18(11), 1791; https://doi.org/10.3390/cancers18111791 (registering DOI)
Submission received: 26 April 2026
/
Revised: 22 May 2026
/
Accepted: 26 May 2026
/
Published: 30 May 2026
(This article belongs to the Special Issue Feature Papers in Section "Tumor Microenvironment" (2nd Edition))
Simple Summary
Tumor progression and metastasis depend on a dynamic and reciprocal interaction between cancer cells and their surrounding environment, yet the mechanisms by which these complex processes are coordinated at the cell surface are not fully understood. Clusterin, a protein secreted outside cells, may play key roles in integrating these events, helping the assembly of key molecules on the cell membrane into a functional network that links extracellular matrix remodeling, endocytosis, and intracellular signaling. Through this organization, clusterin may promote changes in cell shape and behavior that promote cancer cell migration and invasion. By proposing this model, we aim to provide a new perspective on how these events are regulated and to highlight potential targets for future therapeutic strategies.
Abstract
Tumor cell migration relies on the integration of extracellular matrix (ECM) remodeling, cell surface signaling regulating cytoskeleton dynamics, and epithelial-to-mesenchymal transition (EMT). Clusterin (CLU), a secreted glycoprotein, is involved in extracellular proteostasis and is known to interact with members of the LDL receptor family, including low-density lipoprotein receptor-related protein 1 (LRP1). Beyond its canonical chaperone activity, CLU is involved in several biological processes, including cell survival, apoptosis, tissue remodeling, inflammation and cancer progression. On the other hand, the membrane type 1 matrix metalloproteinase (MT1-MMP), functionally linked to CD44 and LRP1, represents a key membrane-associated molecule that may control cell adhesion and receptor-mediated uptake of ECM ligands and proteases. In this article, we critically highlight a hypothetical model in which secreted CLU (sCLU) may function as the central player of a dynamic membrane-associated network integrating proteolysis, endocytosis, and intracellular signaling. Based on recent literature findings and STRING analyses, LRP1, MT1-MMP, CD44, and cell surface matrix components, such as proteoglycans (PGs) and integrins, are likely to be involved. By coordinating this membrane-associated molecular crosstalk, sCLU may integrate ECM remodeling with cytoskeletal dynamics and EMT-related programs related to invasive behavior. Overall, this framework highlights a potential mechanism through which sCLU may contribute to tumor cell plasticity and aggressiveness, suggesting new avenues for therapeutic intervention.
