# Cancer-Associated Fibroblasts Move and Interact More with Triple-Negative Breast Cancer Cells and Stimulate Their Proliferation in a Hyaluronan-Dependent Manner

## TL;DR

Cancer-associated fibroblasts in triple-negative breast cancer produce more hyaluronan, which helps them mix with cancer cells and promote tumor growth.

## Contribution

The study reveals that hyaluronan production by cancer-associated fibroblasts drives tumor progression in triple-negative breast cancer.

## Key findings

- Cancer-associated fibroblasts from triple-negative breast cancer secrete higher hyaluronan than normal fibroblasts.
- Hyaluronan enables fibroblasts to mix with cancer cells and boost their proliferation.
- Reducing hyaluronan synthase 2 decreases the stimulation of cancer cell growth by fibroblasts.

## Abstract

What are the main findings?
Cancer-associated fibroblasts from Triple-negative breast cancer secrete high levels of hyaluronan, compared with normal breast fibroblasts, altering the tumour microenvironment.Hyaluronan production by Triple-negative breast cancer-associated fibroblasts enhances mixing of Triple-negative breast cancer cells with fibroblasts and promotes progression of this aggressive cancer type.

Cancer-associated fibroblasts from Triple-negative breast cancer secrete high levels of hyaluronan, compared with normal breast fibroblasts, altering the tumour microenvironment.

Hyaluronan production by Triple-negative breast cancer-associated fibroblasts enhances mixing of Triple-negative breast cancer cells with fibroblasts and promotes progression of this aggressive cancer type.

What is the implication of the main finding?
Inhibition of the production of hyaluronan by Triple-negative breast cancer-associated fibroblasts is a potential future therapeutic target against Triple-negative breast cancer progression.

Inhibition of the production of hyaluronan by Triple-negative breast cancer-associated fibroblasts is a potential future therapeutic target against Triple-negative breast cancer progression.

While normal fibroblasts suppress tumor growth, during cancer initiation and progression, this capacity can be lost and even switched to tumor-promoting, for reasons that are not understood. In this study, we aimed to determine differences between patient-derived cancer-associated fibroblasts and fibroblasts from healthy breast tissue to identify if and how these changes stimulate Triple-negative breast cancer (TNBC). Two-dimensional and three-dimensional mono and co-cultures of TNBC cells with fibroblasts from healthy breast or TNBC were analyzed for cell contractility, migration, distribution, proliferation, and hyaluronan production by traction force microscopy, live cell imaging, flow cytometry, Western blot, and ELISA. In 3D spheroid co-culture, CAFs migrated into the tumor mass, mixing with tumor cells, whereas normal fibroblasts remained separate. In 2D, CAFs showed increased cell migration and contractile force, and, in both 2D and 3D co-culture, CAFs increased the proliferation of TNBC cells. CAFs showed increased production of hyaluronan, as compared to normal fibroblasts, and loss of hyaluronan synthase 2 reduced CAF-induced stimulation of TNBC proliferation. These findings suggest that increased production of hyaluronan by TNBC CAFs enhances their capacity to mix with and induce the proliferation of cancer cells, and that the production of hyaluronan by CAFs can be a future therapeutic target against TNBC.