Stromal cells regulate mechanics of tumour spheroid

Ayushi Agrawal; Soufian Lasli; Yousef Javanmardi; Diane Coursier; Auxtine Micalet; Sara Watson; Somayeh Shahreza; Bianca Serwinski; Boris Djordjevic; Nicolas Szita; Umber Cheema; Sergio Bertazzo; Fernando Calvo; Emad Moeendarbary

doi:10.1016/j.mtbio.2023.100821

Stromal cells regulate mechanics of tumour spheroid

Mater Today Bio. 2023 Oct 6:23:100821. doi: 10.1016/j.mtbio.2023.100821. eCollection 2023 Dec.

Authors

Ayushi Agrawal¹, Soufian Lasli¹, Yousef Javanmardi¹, Diane Coursier², Auxtine Micalet^{1

3}, Sara Watson¹, Somayeh Shahreza¹, Bianca Serwinski^{1

2

4}, Boris Djordjevic^{1

2}, Nicolas Szita⁵, Umber Cheema³, Sergio Bertazzo⁶, Fernando Calvo⁷, Emad Moeendarbary^{1

8}

Affiliations

¹ Department of Mechanical Engineering, University College London, London, WC1E 7JE, UK.
² 199 Biotechnologies Ltd, Gloucester Road, London, W2 6LD, UK.
³ Department of Targeted Intervention, Division of Surgery and Interventional Science, University College London, London WC1E 7JE, UK.
⁴ Faculty of Social Sciences, Northeastern University London, London, E1W 1LP, UK.
⁵ Department of Biochemical Engineering, University College London, London WC1E 7JE, UK.
⁶ Department of Medical Physics and Biomedical Engineering, University College London, London, WC1E 6BT, UK.
⁷ Instituto de Biomedicina y Biotecnología de Cantabria (Consejo Superior de Investigaciones Científicas, Universidad de Cantabria), Santander, Spain.
⁸ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Abstract

The remarkable contractility and force generation ability exhibited by cancer cells empower them to overcome the resistance and steric hindrance presented by a three-dimensional, interconnected matrix. Cancer cells disseminate by actively remodelling and deforming their extracellular matrix (ECM). The process of tumour growth and its ECM remodelling have been extensively studied, but the effect of the cellular tumour microenvironment (TME) has been ignored in most studies that investigated tumour-cell-mediated ECM deformations and realignment. This study reports the integration of stromal cells in spheroid contractility assays that impacts the ECM remodelling and invasion abilities of cancer spheroids. To investigate this, we developed a novel multilayer in vitro assay that incorporates stromal cells and quantifies the contractile deformations that tumour spheroids exert on the ECM. We observed a negative correlation between the spheroid invasion potential and the levels of collagen deformation. The presence of stromal cells significantly increased cancer cell invasiveness and altered the cancer cells' ability to deform and realign collagen gel, due to upregulation of proinflammatory cytokines. Interestingly, this was observed consistently in both metastatic and non-metastatic cancer cells. Our findings contribute to a better understanding of the vital role played by the cellular TME in regulating the invasive outgrowth of cancer cells and underscore the potential of utilising matrix deformation measurements as a biophysical marker for evaluating invasiveness and informing targeted therapeutic opportunities.

Keywords: Cancer spheroids; Contractility; Mechanobiology; Stromal cells; Traction forces.