Force-dependent extracellular matrix remodeling by early-stage cancer cells alters diffusion and induces carcinoma-associated fibroblasts

Wei-Hung Jung; Nicholas Yam; Chin-Chi Chen; Khalid Elawad; Brian Hu; Yun Chen

doi:10.1016/j.biomaterials.2020.119756

Force-dependent extracellular matrix remodeling by early-stage cancer cells alters diffusion and induces carcinoma-associated fibroblasts

Biomaterials. 2020 Mar:234:119756. doi: 10.1016/j.biomaterials.2020.119756. Epub 2020 Jan 8.

Authors

Wei-Hung Jung¹, Nicholas Yam², Chin-Chi Chen³, Khalid Elawad⁴, Brian Hu⁵, Yun Chen⁶

Affiliations

¹ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; The Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Center for Cell Dynamics, Johns Hopkins University, MD, 21205, USA.
² Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; The Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Center for Cell Dynamics, Johns Hopkins University, MD, 21205, USA.
³ Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, 21231, USA.
⁴ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁵ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁶ Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; The Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA; Center for Cell Dynamics, Johns Hopkins University, MD, 21205, USA. Electronic address: yun.chen@jhu.edu.

PMID: 31954229
DOI: 10.1016/j.biomaterials.2020.119756

Abstract

It is known cancer cells secrete cytokines inducing normal fibroblasts (NFs) to become carcinoma-associated fibroblasts (CAFs). However, it is not clear how the CAF-promoting cytokines can effectively navigate the dense ECM, a diffusion barrier, in the tumor microenvironment to reach NFs during the early stages of cancer development. In this study, we devised a 3D coculture system to investigate the possible mechanism of CAF induction at early stages of breast cancer. We found that in a force-dependent manner, ECM fibrils are radially aligned relative to the tumor spheroid. The fibril alignment enhances the diffusion of exosomes containing CAF-promoting cytokines towards NFs. Suppression of force generation or ECM remodeling abolishes the enhancement of exosome diffusion and the subsequent CAF induction. In summary, our finding suggests that early-stage, pre-metastatic cancer cells can generate high forces to align the ECM fibrils, thereby enhancing the diffusion of CAF-promoting exosomes to reach the stroma and induce CAFs.

Keywords: Carcinoma-associated fibroblast; Diffusion; Early-stage cancer; Extracellular matrix remodeling; Tumor microenvironment.

MeSH terms

Cancer-Associated Fibroblasts*
Carcinoma*
Extracellular Matrix
Fibroblasts
Humans
Tumor Microenvironment