Language
English
Publication Date
2-6-2026
Journal
Nature Communications
DOI
10.1038/s41467-026-69007-w
PMID
41651843
PMCID
PMC12881594
PubMedCentral® Posted Date
2-6-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Metastatic tumor cell dissemination is the leading cause of cancer-related deaths. Clustered circulating tumor cells (CTCs) possess higher metastatic potential than single CTCs. Epithelial adherens junction (AJ) proteins typically mediate stable cell-cell interactions; however, these proteins are frequently lost in highly aggressive triple-negative breast cancers (TNBCs), raising the question of how CTCs from such tumors cluster. Here we show that the extracellular matrix (ECM) component hyaluronan (HA) mediates AJ-independent CTC clustering in TNBCs. HA is necessary and sufficient to drive clustering of tumor cells expressing its receptor CD44. Mechanistically, HA initiates contact between neighboring cells through actin-based membrane protrusions. As cells are pulled closer, these initial interactions expand to membrane-membrane contact and are subsequently stabilized by desmosomes. CTC-derived HA also acts as a docking platform to promote heterotypic cluster formation by recruiting non-CTCs, including immune cells. Thus, this ECM-receptor interaction enables CTC clustering and survival under shear stress, enhancing TNBC metastasis.
Keywords
Neoplastic Cells, Circulating, Humans, Triple Negative Breast Neoplasms, Extracellular Matrix, Female, Hyaluronic Acid, Cell Line, Tumor, Hyaluronan Receptors, Neoplasm Metastasis, Animals, Desmosomes, Adherens Junctions, Breast cancer, Metastasis, Extracellular matrix
Published Open-Access
yes
Recommended Citation
Bobkov, Georg Om; Patel, Khushali J; Lege, Bree M; et al., "Extracellular Matrix Mediates Circulating Tumor Cell Clustering in Triple-Negative Breast Cancer Metastasis" (2026). Faculty, Staff and Students Publications. 7097.
https://digitalcommons.library.tmc.edu/baylor_docs/7097