Ho Kenneth K Y, Buschhaus Johanna M, Zhang Anne, Cutter Alyssa C, Humphries Brock A, Luker Gary D
Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Sci Rep. 2025 Aug 13;15(1):29621. doi: 10.1038/s41598-025-14495-x.
Biophysical properties of the extracellular matrix (ECM), such as mechanical stiffness, directly regulate behaviors of cancer cells linked to cancer initiation and progression. Cells sense and respond to ECM stiffness in the context of dynamic changes in biochemical inputs, such as growth factors and chemokines. While commonly studied as isolated inputs, mechanisms by which combined effects of mechanical stiffness and biochemical factors affect functions of cancer cells remain poorly defined. Using a combination of elastically supportive surface (ESS) culture dishes with defined stiffnesses and single-cell imaging, we report here that culturing cells on a stiff (28 kPa) versus soft (1.5 kPa) substrate increases CXCR4 and EGFR expression and promotes greater ligand-dependent internalization of CXCR4. In addition to increased CXCR4 expression, a stiff ECM also increases basal activation of Akt and ERK as well as signaling through these kinases in response to CXCL12-α and EGF and promotes migration of triple negative breast cancer (TNBC) cells. These data implicate receptor dynamics as a key mediator of Akt and ERK signaling as a mechanism for adverse effects of enhanced ECM stiffness on disease progression in TNBC.
细胞外基质（ECM）的生物物理特性，如机械硬度，直接调节与癌症起始和进展相关的癌细胞行为。细胞在生物化学输入（如生长因子和趋化因子）的动态变化背景下感知并响应ECM硬度。虽然通常作为孤立的输入进行研究，但机械硬度和生物化学因素的联合作用影响癌细胞功能的机制仍不清楚。通过结合具有确定硬度的弹性支撑表面（ESS）培养皿和单细胞成像，我们在此报告，在坚硬（28kPa）与柔软（1.5kPa）的基质上培养细胞会增加CXCR4和EGFR的表达，并促进CXCR4更大程度的配体依赖性内化。除了CXCR4表达增加外，坚硬的ECM还会增加Akt和ERK的基础激活以及响应CXCL12-α和EGF时通过这些激酶的信号传导，并促进三阴性乳腺癌（TNBC）细胞的迁移。这些数据表明受体动力学是Akt和ERK信号传导的关键介质，是ECM硬度增强对TNBC疾病进展产生不利影响的一种机制。
