Agrawal Ayushi, Lasli Soufian, Javanmardi Yousef, Coursier Diane, Micalet Auxtine, Watson Sara, Shahreza Somayeh, Serwinski Bianca, Djordjevic Boris, Szita Nicolas, Cheema Umber, Bertazzo Sergio, Calvo Fernando, Moeendarbary Emad
Department of Mechanical Engineering, University College London, London, WC1E 7JE, UK.
199 Biotechnologies Ltd, Gloucester Road, London, W2 6LD, UK.
Mater Today Bio. 2023 Oct 6;23:100821. doi: 10.1016/j.mtbio.2023.100821. eCollection 2023 Dec.
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 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.
癌细胞所展现出的显著收缩性和力量生成能力，使它们能够克服三维相互连接基质所呈现的阻力和空间位阻。癌细胞通过积极重塑和变形其细胞外基质（ECM）来实现扩散。肿瘤生长过程及其ECM重塑已得到广泛研究，但在大多数研究肿瘤细胞介导的ECM变形和重新排列的研究中，细胞肿瘤微环境（TME）的影响被忽视了。本研究报告了在球体收缩性测定中整合基质细胞，这会影响癌球体的ECM重塑和侵袭能力。为了对此进行研究，我们开发了一种新型多层测定法，该方法纳入了基质细胞，并量化肿瘤球体对ECM施加的收缩变形。我们观察到球体侵袭潜力与胶原蛋白变形水平之间呈负相关。由于促炎细胞因子的上调，基质细胞的存在显著增加了癌细胞的侵袭性，并改变了癌细胞使胶原蛋白凝胶变形和重新排列的能力。有趣的是，在转移性和非转移性癌细胞中均一致观察到这一现象。我们的研究结果有助于更好地理解细胞TME在调节癌细胞侵袭性生长中所起的关键作用，并强调利用基质变形测量作为评估侵袭性和提供靶向治疗机会的生物物理标志物的潜力。
