# Extracellular matrix mediates circulating tumor cell clustering in triple-negative breast cancer metastasis

## TL;DR

This paper shows how tumor cells in aggressive breast cancer form clusters using hyaluronan, which helps them spread more effectively.

## Contribution

The study reveals a novel ECM-mediated mechanism for CTC clustering in TNBCs lacking epithelial adhesion proteins.

## Key findings

- Hyaluronan (HA) mediates CTC clustering independently of epithelial adherens junction proteins.
- HA initiates cell-cell contact via actin-based protrusions and stabilizes interactions through desmosomes.
- HA also promotes heterotypic clusters by recruiting non-CTC cells like immune cells.

## 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.

Circulating tumor cell (CTC) clusters are key drivers of metastasis, yet their formation in tumors lacking classical adhesion molecules is unclear. Here, the authors discover that hyaluronic acid promotes homotypic and heterotypic CTC clustering by initiating early cell contacts and stabilizing mature interactions.